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CORK Bibliography: Therapeutic Use of Marijuana and Other Drugs

70 citations. January 2010 to present

Prepared: March 2012

Andolfatto G; Willman E. A prospective case series of single-syringe ketamine-propofol (Ketofol) for emergency department procedural sedation and analgesia in adults. Academic Emergency Medicine 18(3): 237-245, 2011. (52 refs.)

Objectives: The objective was to evaluate the effectiveness, recovery time, and adverse event profile of intravenous (IV) mixed 1:1 ketamine-propofol (ketofol) for adult procedural sedation and analgesia (PSA) in the emergency department (ED). Methods: Prospective data were collected on all PSA events over a 4.5-year period in a trauma-receiving suburban teaching hospital. PSAs using a 1:1 single-syringe mixture of 10 mg/mL ketamine and 10 mg/mL propofol in patients over 21 years of age were analyzed. Physiologic data, drug doses, adverse events, recovery time, patient satisfaction, and staff satisfaction were recorded. Results: Ketofol PSA was used in 728 patients for primarily orthopedic procedures. Median patient age was 53 years (range = 21 to 99 years, interquartile range [IQR] = 36-70 years). The median dose of ketamine and propofol was 0.7 mg/kg each (range = 0.2 to 2.7 mg/kg, IQR = 0.5-0.9 mg/kg), and median recovery time was 14 minutes (range = 3 to 50 minutes, IQR = 10-17 minutes). PSA was effective in 717 cases (98%). Bag-mask ventilation occurred in 15 patients (2.1%; 95% confidence interval [CI] = 1.0% to 3.1%). Recovery agitation occurred in 26 patients (3.6%; 95% CI = 2.2% to 4.9%), of whom 13 (1.8%; 95% CI = 0.8% to 2.7%) required treatment. One patient experienced vomiting and one patient was admitted to the hospital for monitoring of transient dysrhythmia and hypotension. No sequelae were identified. The median staff satisfaction scores were 10 (IQR = 9-10) on a scale of 1 to 10, and 97% of patients would have chosen the same method of PSA in the future. Conclusions: Ketofol is an effective PSA agent in adult ED patients. Recovery times are short and adverse events are few. Patients and ED staff were highly satisfied.

Arroyo-Novoa CM; Figueroa-Ramos MI; Miaskowski C; Padilla G; Paul SM; Rodriguez-Ortiz P et al. Efficacy of small doses of ketamine with morphine to decrease procedural pain responses during open wound care. Clinical Journal of Pain 27(7): 561-566, 2011. (32 refs.)

Objective: The purpose of this study was to evaluate differences in pain intensity, pain quality, physiological measures, and adverse effects when patients received morphine with saline (MS) compared with morphine and a small dose of ketamine (MK) before an open wound care procedure (WCP). Methods: A randomized, cross-over design was used to determine whether the addition of a small dose of ketamine would potentiate morphine's analgesic effects and decrease WCP pain intensity. Patients were randomized to receive either 0.1 mg/kg of morphine (8 mg maximum) plus saline intravenously (IV) or 0.05 mg/kg of morphine (4 mg maximum) plus ketamine 0.25 mg/kg IV before the WCP. Patients were crossed-over to receive the alternate treatment during the next WCP. Results: Eleven male patients participated in the study. Mean rank of pain intensity during WCP-MK was significantly less than during WCP-MS (P = 0.005). Mean +/- standard error of mean pain intensity during the WCP-MK was 3.09 +/- 0.99, whereas it was 6.82 +/- 0.92 during the WCP-MS. However, 91% of the patients had adverse effects (eg, strange sensations, hallucinations, blurred vision) with MK versus 0% with MS. Diastolic blood pressure was significantly higher during the WCP-MK. Discussion: Ketamine with morphine significantly reduced procedural wound pain intensity during WCP. Adverse effects and higher diastolic BP occurred with MK. Further research is warranted to determine the optimal analgesic dose of ketamine or if the addition of a benzodiazepine would mitigate the psychotomimetic effects of ketamine.

Barth KS; Becker WC; Wiedemer NL; Mavandadi S; Oslin DW; Meghani SH et al. Association between urine drug test results and treatment outcome in high-risk chronic pain patients on opioids. Journal of Addiction Medicine 4(3): 167-173, 2010. (32 refs.)

Objective: How to best use urine drug test (UDT) results in the management of opioid pharmacotherapy has not been elucidated. The purpose of this study was to describe how the results of UDTs gathered from a group of chronic pain patients in a high-risk monitored opioid pharmacotherapy program apply to treatment outcome. Methods: Retrospective review of the medical records of 335 primary care patients on chronic opioids more than 22 months. Results: Patients with a UDT containing unprescribed opioids were more likely to demonstrate resolution of aberrant behavior (P = 0.02) and less likely to be discharged from treatment (P = 0.04). Patients with cocaine, alone or in combination, in the UDT were less likely to resolve aberrant behavior (P = 0.007 and 0.001), and were more likely to be electively or administratively discharged from treatment (P = 0.012 and 0.001). Discussion: In this group of high-risk pain patients on chronic opioids, information gained from UDT results can be used to predict treatment outcomes and inform appropriate interventions. Patients on chronic opioids who have a UDT positive for an illicit opioid or unprescribed opioids alone are more likely to respond to monitored opioid pharmacotherapy. Patients with a UDT positive for cocaine, alone or in combination, are less likely to resolve aberrant behavior within the structure of a monitored opioid pharmacotherapy program and are more likely to be discharged electively or administratively from the program without significant transition to addiction treatment. Further studies are needed to investigate which patient responded best to structured opioid pharmacotherapy programs and how to appropriately handle abnormal UDT results to improve the management and engagement in appropriate treatment for this population.

Carhart-Harris RL; Nutt DJ. User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study. Journal of Substance Use 15(4): 283-300, 2010. (32 refs.)

This study used a web-based questionnaire to investigate user perceptions of the benefits and harms of hallucinogenic drug use. Over 600 forms were submitted. Users were asked to comment on the acute and prolonged effects of different drugs and to provide more specific information on how particular drugs have harmed and/or helped them. Subjects reported relatively less harm associated with the classic hallucinogens, LSD and psilocybin, than other drugs specifically focused on in the questionnaire (MDMA, cannabis, ketamine and alcohol). A wide-range of benefits was reported, including: help with mood disorders, addictions and migraine as well as more general long-term improvements in wellbeing. Symptoms of hallucinogen persisting perceptual disorder were reported by a number of subjects and these were most closely associated with use of LSD; however, few users regarded these effects as troubling. Eighty-one per cent of users reported having had a 'spiritual experience' on a hallucinogenic drug and over 90% considered 'access to the unconscious mind' to be a specific property of the classic hallucinogens. With caution, these findings support recent calls for a systematic investigation of the therapeutic potential of the classic hallucinogens and highlight the scope for empirical investigations of spiritual and psychodynamic phenomena.

Castells X; Ramos-Quiroga JA; Bosch R; Nogueira M; Casas M. Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults. (review). Cochrane Database of Systematic Reviews (6): e-articleCD007813, 2011. (79 refs.)

Background: Attention Deficit Hyperactivity Disorder (ADHD) is a childhood onset disorder that can persist into adulthood. Amphetamines are used to treat adult ADHD, but uncertainties persist about their efficacy and safety. Objectives: To examine the efficacy and safety of amphetamines for adults with ADHD, as well as the influence of dose, drug type and release formulation type. Search strategy: We searched CENTRAL, PubMedicine, EMBASE, CINAHL, PsycINFO, clinicaltrials. gov, UK Clinical Trials Gateway and references obtained from articles and experts in the field. We conducted the electronic searches on 25 February 2010. Selection criteria: Randomized controlled trials comparing the efficacy of amphetamine derivatives against placebo or an active intervention. Data collection and analysis: Two authors extracted data from each included study. We used the standardized mean difference ( SMD) and the risk ratio ( RR) to assess continuous and dichotomous outcomes, respectively. We conducted a stratified analysis to determine the influence of moderating variables. We assessed the trials for risk of bias and drew a funnel plot to investigate the possibility of publication bias. Main results: We included seven studies, which enrolled 1091 participants. All studies were placebo-controlled and three included an active comparator: guanfacine, modafinil and paroxetine. Most studies had short-term follow-up, with a mean study length of 8.1 weeks. Amphetamines improved ADHD symptom severity (SMD = -0.72; 95% CI -0.87 to -0.57) but did not improve retention in treatment overall and were associated with increased dropout due to adverse events (RR 3.03; 95% CI 1.52 to 6.05). The three amphetamine derivatives investigated (dextroamphetamine, lisdexamphetamine and mixed amphetamine salts (MAS)) were all efficacious for reducing ADHD symptoms, but MAS also increased retention in treatment. Different doses did not appear associated with differences in efficacy. We investigated immediate and sustained drug release formulations but found no difference between them on any outcome. When amphetamines were compared to other drug interventions, no differences were found. We did not find any study to be at low risk of bias overall, mainly because amphetamines have powerful subjective effects that may reveal the assigned treatment. Authors' conclusions: Amphetamines improved short-term ADHD symptom severity. MAS also increased retention in treatment. Amphetamines were associated with higher attrition due to adverse events. The short study length and the restrictive inclusion criteria limit the external validity of these findings. Furthermore, the possibility that the results of the included studies were biased was high, which could have led to an overestimation of amphetamine efficacy.

Chan BKB; Tam LK; Wat CY; Chung YF; Tsui SL; Cheung CW. Opioids in chronic non-cancer pain. (review). Expert Opinion on Pharmacotherapy 12(5): 705-720, 2011. (132 refs.)

Introduction: The use of chronic opioid therapy for chronic non-cancer pain is growing and is now accepted as an effective treatment modality. Areas covered: Although there are guidelines and reviews for chronic opioid therapy for chronic non-cancer pain patients, physicians may still have concerns and be reluctant to prescribe strong opioids for chronic non-cancer pain. Common issues and concerns when prescribing opioid for chronic pain management are reviewed and discussed. The literature search was done using Medline with key words "chronic non-cancer pain", "chronic opioid therapy", "effectiveness", "opioid tolerance", "opioid-induced hyperalgesia", "adverse effect", "opioid dependency", "addiction", "monitoring", "opioid contract" and various combinations with these key words. Studies from 1990 -- 2010 have been included. This article helps readers to update, clarify and understand the common concerns when using opioid for chronic non-cancer pain. Clinical effectiveness and adverse effects with chronic opioid therapy, opioid tolerance and opioid-induced hyperalgesia, opioid dependency and addiction, monitoring during chronic opioid use, and opioid contact are discussed in detailed. Expert opinion: Not much strongly positive data supports the long-term use of opioids for pain relief, and the evidence for an improvement in functional activity is inconclusive. With careful selection of patients, meticulous prescription and monitoring protocol, chronic non-cancer pain patients who are likely to benefit from potent opioids should not be prevented from obtaining this treatment.

Ciancio G; Colina M; La Corte R; Lo Monaco A; De Leonardis F; Trotta F et al. Nicotine-patch therapy on mucocutaneous lesions of Behcet's disease: A case series. Rheumatology 49(3): 501-504, 2010. (18 refs.)

Objective. We report the use of nicotine-patch therapy on active mucocutaneous lesions of Behcet's disease (BD). Methods. Five BD ex-smoker patients with refractory active mucocutaneous manifestations were treated with nicotine patches for 6 months. Results. Four out of five patients quickly responded to nicotine-patch therapy and experienced a complete regression of mucocutaneous lesions. Other manifestations of BD did not respond and new manifestations appeared during this treatment. One patient had no benefit from therapy but on restarting smoking it was promptly effective. Conclusions. Mucocutaneous lesions associated with BD may be modulated by smoking. Both smoking and nicotine-replacement therapy may be efficacious not only on oral aphthae, but also on other mucocutaneous manifestations, whereas the efficacy in the treatment and prevention of other systemic manifestations of BD is not proven. At least in ex-smokers, nicotine in its pure form is well tolerated and its use could be justified in selected cases of BD with predominant and recurrent refractory mucocutaneous manifestations.

Claire LS; Stothart G; McKenna L; Rogers PJ. Caffeine abstinence: An ineffective and potentially distressing tinnitus therapy. International Journal of Audiology 49(1): 24-29, 2010. (27 refs.)

The effect of phased caffeine withdrawal and abstention on tinnitus severity was assessed using a pseudo-randomized, double-blinded, placebo-controlled crossover trial of 30 days duration. Sixty-six volunteers who experienced tinnitus and who usually consumed at least 150 mg/day of caffeine participated. The intervention was a direct replacement of usual caffeinated tea/coffee with double-blinded supplies, under one of two conditions. Condition 1: Maintenance followed by phased withdrawal. Condition 2: Phased withdrawal followed by reintroduction and maintenance. Tinnitus severity was measured by the total score of the Tinnitus Questionnaire on Days 1, 15, and 30. Secondary measures included twice daily self-rated symptoms relevant to tinnitus and caffeine withdrawal. Caffeine had no effect on tinnitus severity, the mean difference between caffeinated and decaffeinated days being-0.04 (95% confidence interval -1.99 to 1.93), p=0.97. Significant acute adverse symptoms of caffeine withdrawal were observed. No evidence was found to justify caffeine abstinence as a therapy to alleviate tinnitus, but acute effects of caffeine withdrawal might add to the burden of tinnitus.

Cockburn A. Marijuana, boom and bust. (editorial). Nation 290(15): 9-9, 2010. (0 refs.)

In this article the author discusses marijuana production in the northern California region of Humboldt County. The history of marijuana in the area is discussed beginning in the 1970s and running through to April 2010. A number of issues are addressed including the attempts by authorities to curtail drug production, the economic advantages of the war on drugs, and the campaign for the use of medical marijuana started by Dennis Peron. The author envisions an era when northern California will be less prosperous because of the legalization of cannabis.

Cohen PJ. Medical marijuana 2010: It's time to fix the regulatory vacuum. Journal of Law, Medicine & Ethics 38(3): 654-666, 2010. (21 refs.)

This article examines the history of assigning a banned status to medical marijuana; describes the politics of medical marijuana research; provides evidence of the scientifically demonstrated efficacy and safety of Cannabis for certain pathologic conditions; analyzes several vaguely worded state statutes governing the recommendation, distribution, and use of "medical marijuana" that render its use open to abuse; and recommends the development and enforcement of statutory and regulatory reforms that would bring state oversight of this drug into agreement with stringent federal regulation of other controlled substances with proven medical utility.

Czarnetzki C; Schiffer E; Lysakowski C; Haller G; Bertrand D; Tramer MR. Transcutaneous nicotine does not prevent postoperative nausea and vomiting: A randomized controlled trial. British Journal of Clinical Pharmacology 71(3): 383-390, 2011. (19 refs.)

There is empirical evidence that smokers are less likely to suffer from postoperative nausea and vomiting (PONV). center dot Tobacco smoke is known to induce enzymes, for instance, cytochrome P450, and this may partially explain the PONV-protecting effect of smoking. center dot Chronic exposure to nicotine that is contained in the tobacco may lead to a desensitization of central nicotine receptors, and, subsequently, to an increased tolerance to the emetogenic effects of surgery and anaesthesia. WHAT THIS STUDY ADDS: center dot In non-smokers undergoing surgery under general anaesthesia, pre-operatively administered transcutaneous nicotine did not decrease the incidence of PONV within 24 h. center dot Patients receiving nicotine had a tendency to develop PONV symptoms earlier than controls. center dot Exposure to transcutaneous nicotine significantly increased the risk of insomnia during the first postoperative night. AIMS: There is empirical evidence that smokers are less likely to suffer from postoperative nausea and vomiting (PONV). We sought to investigate whether transcutaneus nicotine prevents PONV. METHODS: Non-smokers receiving general anaesthesia for surgery were randomly allocated to Nicotinell (R) Patch 10 cm2 (TTS 10), containing 17.5 mg of nicotine (average delivery rate, 7 mg 24 h-1) or matching placebo patch. Patches were applied 1 h before surgery and were left in situ until 24 h after surgery (or until the first PONV symptoms occurred). RESULTS: We randomized 90 patients (45 nicotine, 45 placebo). In the post-anaesthetic care unit, the incidence of nausea was 22.2% with nicotine and 24.4% with placebo (P = 0.80), and the incidence of vomiting was 20.0% with nicotine and 17.8% with placebo (P = 0.78). Cumulative 24 h incidence of nausea was 42.2% with nicotine and 40.0% with placebo (P = 0.83), and of vomiting was 31.1% with nicotine and 28.9% with placebo (P = 0.81). PONV episodes tended to occur earlier in the nicotine group. Postoperative headache occurred in 17.8% of patients treated with nicotine and in 15.6% with placebo (P = 0.49). More patients receiving nicotine reported a low quality of sleep during the first postoperative night (26.7% vs. 6.8% with placebo; P = 0.01). CONCLUSIONS: Non-smokers receiving a prophylactic nicotine patch had a similar incidence of PONV during the first 24 h and tended to develop PONV symptoms earlier compared with controls. They had a significantly increased risk of insomnia during the first postoperative night.

Davey M. Theme: Ketamine use and abuse. (editorial). Emergency Medicine Journal 28(7): 552-636, 2011. (13 refs.)

Diep F. Pharmaceuticals: Clearing the smoke. Marijuana remains tightly controlled, even though its compounds show promise. (editorial). Scientific American 305(4): 21, 2011. (0 refs.)

Doyle LW; Cheong J; Hunt RW; Lee KJ; Thompson DK; Davis PG et al. Caffeine and brain development in very preterm infants. Annals of Neurology 68(5): 734-742, 2010. (36 refs.)

Objective: Caffeine improves neurological outcome in very preterm infants, but the mechanisms responsible for this neurological benefit are unknown. The objective of this study was to assess whether caffeine influenced brain macro-or microstructural development in preterm infants. Methods: Seventy preterm infants <1,251 g birthweight randomly allocated to either caffeine (n = 33) or placebo (n = 37) underwent brain magnetic resonance imaging (MRI) at term-equivalent age; white and gray matter abnormalities were qualitatively scored, global and regional brain volumes were measured, and white matter microstructure was evaluated using diffusion-weighted imaging. Results: There were no significant differences between the groups in the extent of white matter or gray matter abnormality, or in global or regional brain volumes. In contrast, although only available in 28 children, caffeine exposure was associated with reductions in the apparent diffusion coefficient, and radial and axial diffusivity with the greatest impact in the superior brain regions. The alterations in diffusion measures were not mediated by lowering the rate of lung injury, known as bronchopulmonary dysplasia. Interpretation: These diffusion changes are consistent with improved white matter microstructural development in preterm infants who received caffeine.

Duff M; Elkhodair S. Caffeine in the treatment of post lumbar puncture headache. (editorial). Emergency Medicine Journal 27(6): 477-477, 2010. (2 refs.)

Edlund MJ; Martin BC; Fan MY; Devries A; Braden JB; Sullivan MD. Risks for opioid abuse and dependence among recipients of chronic opioid therapy: Results from the TROUP Study. Drug and Alcohol Dependence 112(1-2): 90-98, 2010. (54 refs.)

Objective: To estimate the prevalence of and risk factors for opioid abuse/dependence in long-term users of opioids for chronic pain, including risk factors for opioid abuse/dependence that can potentially be modified to decrease the likelihood of opioid abuse/dependence, and non-modifiable risk factors for opioid abuse/dependence that may be useful for risk stratification when considering prescribing opioids. Methods: We used claims data from two disparate populations, one national, commercially insured population (HealthCore) and one state-based, publicly insured (Arkansas Medicaid). Among users of chronic opioid therapy, we regressed claims-based diagnoses of opioid abuse/dependence on patient characteristics, including physical health, mental health and substance abuse diagnoses, sociodemographic factors, and pharmacological risk factors. Results: Among users of chronic opioid therapy, 3% of both the HealthCore and Arkansas Medicaid samples had a claims-based opioid abuse/dependence diagnosis. There was a strong inverse relationship between age and a diagnosis of opioid abuse/dependence. Mental health and substance use disorders were associated with an increased risk of opioid abuse/dependence. Effects of substance use disorders were especially strong, although mental health disorders were more common. Concerning opioid exposure; lower days supply, lower average doses, and use of Schedule III-IV opioids only, were all associated with lower likelihood of a diagnosis of opioid abuse/dependence. Conclusion: Opioid abuse and dependence are diagnosed in a small minority of patients receiving chronic opioid therapy, but this may under-estimate actual misuse. Characteristics of the patients and of the opioid therapy itself are associated with the risk of abuse and dependence.

Franck LS; Scoppettuolo LA; Wypij D; Curley MAQ. Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain 153(1): 142-148, 2012. (26 refs.)

Critically ill pediatric patients frequently receive prolonged analgesia and sedation to provide pain relief and facilitate intensive care therapies. Iatrogenic withdrawal syndrome occurs when these drugs are stopped abruptly or weaned too rapidly. We investigated the validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) in children during weaning of analgesics and sedatives. Of 308 children initially supported on mechanical ventilation for acute respiratory failure, 126 (41%) from 21 centers (median age 1.6 years; interquartile range 0.6-7.7 years) were exposed to 5 or more days of opioids. Subjects were assessed for withdrawal symptoms with the WAT-1, an 11-item (12-point) scale, from the first day of weaning from analgesia/sedation until 72 h after the last opioid dose. A total of 836 daily WAT-1 assessments were completed, with a median (interquartile range) WAT-1 score of 2 (0-4) over 6 (3-9) days per subject. There were no significant differences in WAT-1 scores as a function of age. Factor analyses confirmed that motor-related symptoms and behavioral state accounted for the most variance in WAT-1 scores. Supporting construct validity, cumulative opioid exposures were greater [40.2 (19.7-83.4) vs 17.6 (14.6-39.7) mg/kg, P = .004], length of opioid treatment before weaning was longer [7 (611) vs 5 (5-8) days, P = .004], and length of weaning from opioids was longer [10 (6-14) vs 6 (3-9) days, P = .008] in subjects with WAT-1 scores of >= 3 compared to subjects with WAT-1 scores of < 3. The WAT-1 shows good psychometric performance and generalizability when used to assess clinically important withdrawal symptoms in pediatric intensive care and general ward settings.

Gadit AAM. Medical marijuana: Can we think about it? (editorial). Journal of the Pakistan Medical Association 61(9): 932-933, 2011. (9 refs.)

Gamage TF; Lichtman AH. The endocannabinoid system: Role in energy regulation. (review). Pediatric Blood & Cancer 58(1): 144-148, 2012. (84 refs.)

Cannabis sativa has been used since antiquity to treat many ailments, including eating disorders. The primary psychoactive constituent of this plant, Delta(9)-tetrahydrocannabinol (THC) is an FDA approved medication to treat nausea and emesis caused by cancer chemotherapeutic agents as well as to stimulate appetite in AIDS patients suffering from cachexia. The effects of THC are mediated through the endocannabinoid system (ECS), which promotes a positive energy balance through stimulation of appetite as well as shifting homeostatic mechanisms toward energy storage. Here we discuss the physiological function of the ECS in energy balance and the therapeutic potential of targeting this system.

Glausser W. Cultural Encyclopedia of LSD. New York: McFarland, 2011

This is an encylopedia with over 400 entries. It covers the discovery of LSD by Albert Hoffman, when he accidentally absorbed a small quantity through his fingertips. It covers early the early scientific studies and its emergence into the popular culture in the 1960s. The entries document the influence of LSD on diverse aspects of culture, from psychiatry, to religion, philosophy, arts, entertainment and sports, to commerce, science, politics and espionage. Coverage concentrates on the peak period of 1965 to 1969, but in addition to LSD�s early years also discusses later influences.

Gordon A; Callaghan D; Spink D; Cloutier C; Dzongowski P; O'Mahony W et al. Buprenorphine transdermal system in adults with chronic low back pain: A randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. Clinical Therapeutics 32(5): 844-860, 2010. (49 refs.)

Background: Buprenorphine is a mixed-activity, partial p-opioid agonist. Its lipid solubility makes it well suited for transdermal administration. Objective: This study assessed the efficacy and safety profile of a 7-day buprenorphine transdermal system (BIDS) in adult (age >18 years) patients with moderate to severe chronic low back pain previously treated with tablet daily of an opioid analgesic. Methods: This was a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. After a 2- to 7-day washout of previous opioid therapy, eligible patients were randomized to receive BTDS 10 mu g/h or matching placebo patches. The dose was titrated weekly using 10- and 20-mu g/h patches (maximum, 40 mu g/h) based on efficacy and tolerability. After 4 weeks, patients crossed over to the alternative treatment for another 4 weeks. Patients who completed the double-blind study were eligible to enter the 6-month open-label phase. Rescue analgesia was provided as acetaminophen 325 mg to be taken as 1 or 2 tablets every 4 to 6 hours as needed. The primary outcome assessments were daily pain intensity, measured on a 100-mm visual analog scale (VAS), from no pain to excruciating pain, and a 5-point ordinal scale, from 0 = none to 4 = excruciating. Secondary outcome assessments included the Pain and Sleep Questionnaire (100-mm VAS, from never to always), Pain Disability Index (ordinal scale, from 0 = no disability to 11 = total disability), Quebec Back Pain Disability Scale (categorical scale, from 0 = no difficulty to 5 = unable to do), and the 36-item Short Form Health Survey (SF-36). Patients and investigators assessed overall treatment effectiveness at the end of each phase; they assessed treatment preference at the end of double-blind treatment. After implementation of a precautionary amendment, the QTc interval was measured 3 to 4 days after randomization and after any dose adjustment. All assessments performed during the double-blind phase were also performed every 2 months during the open-label extension. Adverse events were collected by non-directed questioning throughout the study. Results: Of 78 randomized patients, 52 (66.7%) completed at least 2 consecutive weeks of treatment in each study phase without major protocol violations (per-protocol [PP] population: 32 women, 20 men; mean [SD] age, 51.3 [11.4] years; mean weight, 85.5 [19.5] kg; 94% white, 4% black, 2% other). The mean (SD) dose of study medication during the last week of treatment was 29.8 (12.1) mu g/h for BTDS and 32.9 (10.7) mu g/h for placebo (P = NS). During the last week of treatment, BTDS was associated with significantly lower mean (SD) pain intensity scores compared with placebo on both the VAS (45.3 [21.3] vs 53.1 [24.3] mm, respectively; P = 0.022) and the 5-point ordinal scale (1.9 [0.7] vs 2.2 [0.8]; P = 0.044). The overall Pain and Sleep score was significantly lower with BTDS than with placebo (177.6 [125.5] vs 232.9 [131.9]; P = 0.027). There were no treatment differences on the Pain Disability Index, Quebec Back Pain Disability Scale, or SF-36; however, BTDS was associated with significant improvements compared with placebo on 2 individual Quebec Back Pain Disability Scale items (get out of bed: P = 0.042; sit in a chair for several hours: P = 0.022). Of the 48 patients/physicians in the PP population who rated the effectiveness of treatment, 64.6% of patients (n = 31) rated BTDS moderately or highly effective, as did 62.5% of investigators (n = 30). Among the 50 patients in the PP population who answered the preference question, 66.0% of patients (n = 33) preferred the phase in which they received BTDS and 24.0% (n = 12) preferred the phase in which they received placebo (P = 0.001), with the remainder having no preference; among investigators, 60.0% (n = 30) and 28.0% (n = 14) preferred the BTDS and placebo phases, respectively (P = 0.008), with the remainder having no preference. The mean placebo-adjusted change from baseline in the QTc interval ranged from -0.8 to +3.8 milliseconds (P = NS). BIDS treatment was associated with a significantly higher frequency of nausea (P < 0.001), dizziness (P < 0.001), vomiting (P = 0.008), somnolence (P = 0.020), and dry mouth (P = 0.003), but not constipation. Of the 49. patients completing 8 weeks of double-blind treatment, 40(81.6%) entered the 6-month, open-label extension study and 27 completed it. Improvements in pain scores achieved during the double-blind phase were maintained in these patients. Conclusions: In the 8-week, double-blind portion of this study, BIDS 10 to 40 mu g/h was effective compared with placebo in the management of chronic, moderate to severe low back pain in patients 11 had previously received opioids. The improvements in pain scores were sustained throughout the 6-month, open-label extension.

Green AJ; De-Vries K. Cannabis use in palliative care: An examination of the evidence and the implications for nurses. Journal of Clinical Nursing 19(17-18): 2454-2462, 2010. (57 refs.)

Aim and objective: Examine the pharmaceutical qualities of cannabis including a historical overview of cannabis use. Discuss the use of cannabis as a clinical intervention for people experiencing palliative care, including those with life-threatening chronic illness such as multiple sclerosis and motor neurone disease [amyotrophic lateral sclerosis] in the UK. Background: The non-medicinal use of cannabis has been well documented in the media. There is a growing scientific literature on the benefits of cannabis in symptom management in cancer care. Service users, nurses and carers need to be aware of the implications for care and treatment if cannabis is being used medicinally. Design: A comprehensive literature review. Method: Literature searches were made of databases from 1996 using the term cannabis and the combination terms of cannabis and palliative care; symptom management; cancer; oncology; chronic illness; motor neurone disease/amyotrophic lateral sclerosis; and multiple sclerosis. Internet material provided for service users searching for information about the medicinal use of cannabis was also examined. Results: The literature on the use of cannabis in health care repeatedly refers to changes for users that may be equated with improvement in quality of life as an outcome of its use. This has led to increased use of cannabis by these service users. However, the cannabis used is usually obtained illegally and can have consequences for those who choose to use it for its therapeutic value and for nurses who are providing care. Relevance to clinical practice. Questions and dilemmas are raised concerning the role of the nurse when caring and supporting a person making therapeutic use of cannabis.

Griffiths RR; Grob CS. Hallucinogens as medicine. Scientific American 303(6): 76-79, 2010. (4 refs.)

Hundreds of research reports on hallucinogens appeared during the 1950s and 1960s. Illicit use resulted in outlawing of the drugs. Restrictions on research, moreover, brought studies to a halt. Hints from the early set of studies suggesting that these chemicals might help treat patients with various psychiatric disorders were not pursued because of strictures on research. A new wave of studies on hallucinogens, primarily psilocybin, has begun to address whether the drugs can effectively treat the anxiety of cancer patients or help addicts kick their habits. Early results from new trials point to the promise of these therapies, with some patients reporting profound spiritual experiences and, hence, the ability to make important life changes.

Grob CS; Danforth AL; Chopra GS; Hagerty M; McKay CR; Halberstadt AL et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry 68(1): 71-78, 2011. (37 refs.)

Context: Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the early 1970s, however, political and cultural pressures forced the cessation of all projects. This investigation reexamines a potentially promising clinical application of hallucinogens in the treatment of anxiety reactive to advanced-stage cancer. Objective: To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. Design: A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. Setting: A clinical research unit within a large public sector academic medical center. Participants: Twelve adults with advanced-stage cancer and anxiety. Main Outcome Measures: In addition to monitoring safety and subjective experience before and during experimental treatment sessions, follow-up data including results from the Beck Depression Inventory, Profile of Mood States, and State-Trait Anxiety Inventory were collected unblinded for 6 months after treatment. Results: Safe physiological and psychological responses were documented during treatment sessions. There were no clinically significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 months; the Profile of Mood States identified mood improvement after treatment with psilocybin that approached but did not reach significance. Conclusions: This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. Some of the data revealed a positive trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field.

Hamza H; Bryson EO. Exposure of anesthesia providers in recovery from substance abuse to potential triggering agents. Journal of Clinical Anesthesia 23(7): 552-557, 2011. (14 refs.)

Study Objective: To determine the experience, attitudes, and opinions of anesthesia providers in recovery from addiction to anesthetic agents, who subsequently undergo surgery or who require opioid analgesics for injuries or other conditions. Design: Survey instrument. Setting: Academic medical center. Subjects: Physicians and nurse-anesthetists in recovery in the United States. Measurements: A link to a survey was posted on the Anesthetists in Recovery website on January 17, 2010 and allowed to remain active for a period of one week. The survey also was distributed via email to recovering anesthesiologists in a "snowball sampling" method. Completed surveys were reviewed, and data were compiled using Survey Monkey, with categorical variables described as frequencies and percentages. Main Results: A total of 30 surveys were returned, with 27 (90%) reporting a history of abusing anesthetics or drugs commonly found in the work environment, and 19 (65.5%) reporting abuse of recreational drugs and drugs used during the administration of anesthesia. Twenty-eight (93%) respondents reported finding themselves in a situation that necessitated they receive their former drug of choice for legitimate medical reasons while in recovery. Conclusions: Anesthesia care providers in recovery from addiction to anesthetic agents may undergo subsequent exposure to these agents due to medical necessity. Participation in a program of recovery with support from family members may decrease the risk of relapse but does not eliminate it.

Henderson-Smart DJ; Steer PA. Caffeine versus theophylline for apnea in preterm infants. (review). Cochrane Database of Systematic Reviews 1: CD000273, 2010. (17 refs.)

Background: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia, which may be severe enough to require resuscitation including use of positive pressure ventilation. Two forms of methylxanthine (caffeine and theophylline) have been used to stimulate breathing in order to prevent apnea and its consequences. Objectives: To evaluate the effect of caffeine compared with theophylline treatment on the risk of apnea and use of mechanical ventilation in preterm infants with recurrent apnea. Search strategy: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of electronic databases in August 2009: Oxford Database of Perinatal Trials; Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009); MEDLINE (1966 to April 2009); and EMBASE Drugs and Pharmacology (1990 to April 2009), previous reviews including cross references. Selection criteria: Randomized and quasi-randomized trials comparing caffeine to theophylline for treating apnea in preterm infants and reporting effects on apnea event rates. Data collection and analysis: Each author assessed eligibility and trial quality, extracted data separately and compared and resolved differences. Study authors were contacted for additional information. Main results: Five trials involving a total of 108 infants were included. The quality of most of these small trials was fair to good. No difference in treatment failure rate (less than 50% reduction in apnea/bradycardia) was found between caffeine and theophylline after one to three days treatment (based on two studies) or five to seven days treatment (based on one study). There was no difference in mean apnea rate between caffeine and theophylline groups after one to three days treatment (based on five trials) and five to seven days treatment (based on four trials). Adverse effects, indicated by tachycardia or feed intolerance leading to change in dosing, were lower in the caffeine group (summary relative risk 0.17, 95% CI 0.04 to 0.72). This was reported and consistent in three studies. No trial reported the use of ventilation and no data were available to assess effects on growth and development. Authors' conclusions: Caffeine appears to have similar short-term effects on apnea/bradycardia as does theophylline although caffeine has certain therapeutic advantages over theophylline. Theophylline is associated with higher rates of toxicity. The possibility that higher doses of caffeine might be more effective in extremely preterm infants needs further evaluation in randomized clinical trials.

Hirota K; Lambert DG. Ketamine: New uses for an old drug? (editorial). British Journal of Anaesthesia 107(2): 123-126, 2011. (35 refs.)

Hoffmann DE; Weber E. Medical marijuana and the law. (editorial). New England Journal of Medicine 362(16): 1453-1457, 2010. (4 refs.)

Jackson M. "Divine Stramonium": The rise and fall of smoking for asthma. Medical History 54(2): 171-194, 2010. (93 refs.)

During the nineteenth and early twentieth centuries, one of the commonest remedies for asthma, recommended by doctors and adopted by patients across Europe and North America, was to inhale the smoke from cigarettes or powders containing stramonium and other plant preparations. Increasing reliance on the inhalation of stramonium was the result of a number of cultural, clinical and technological developments: the rising popularity of smoking tobacco, opium, and cannabis; new theories of asthma, which emphasised the primary role of spasmodic bronchoconstriction; and growing commercial interest in the production of inhalers for the delivery of medicines directly to the lungs. From the early decades of the twentieth century, however, the wisdom of smoking for asthma was gradually challenged, not only by shifting theories of asthma, which stressed the pathogenetic importance of allergic inflammation in addition to bronchospasm, but also by the emergence of novel pharmaceutical approaches to treatment, by the definition and statutory regulation of poisons and dangerous drugs, and by the gradual recognition of an association between tobacco smoking and cancer. Although the commercial distribution and public consumption of medicated cigarettes and powders continued, smoking stramonium for asthma was eventually proscribed during the final decades of the twentieth century as the direct product of rising concerns about drug abuse amongst young people. In spite of an expansive literature on the history of tobacco consumption and regulation on both sides of the Atlantic and in spite of accounts of smoking opium and cannabis for both recreational and medical purposes, there has been little historical interest in the therapeutic applications of smoking. This article analyses the rise and fall of the smoking cure for asthma, particularly in the Western medical tradition, within the context of shifting approaches to asthma, the changing fortunes of smoking, and developments in the pharmaceutical industry.

Jaffe SL; Klein M. Medical marijuana and adolescent treatment. American Journal on Addictions 19(5): 460-461, 2010. (2 refs.)

This brief report provides the result of a survey of California child psychiatrists to ascertain changes among their patients' perception of marijuana in the wake of medical marijuana now being available in the state. The survey consisted of 7 questions that touched upon changes in perceptions of availability of marijuana, whether it is seen as more harmful, more beneficial, and whether there was more or less recognition of marijuana's effects on memory, on level of motivation, and more problems complicated by marijuana use. While the response was only 14% or those surveyed, those who responded indicated that their patients have been influenced by the advent of medical marijuana. Those responded indicated that marijuana is seen as more beneficial, and more available. In addition there is decreased recognition of major side effects. It is also noted that adolescents apparently are receiving medical marijuana cards without parental permission.

Jennings PA; Cameron P; Bernard S. Ketamine as an analgesic in the pre-hospital setting: A systematic review. (review). Acta Anaesthesiologica Scandinavica 55(6): 638-643, 2011. (19 refs.)

Background: Pain is a common presenting complaint and there is considerable debate regarding the best practice for analgesia in the pre-hospital environment for trauma patients with severe pain. Methods: A review of the literature was conducted using a number of electronic medical literature databases from their earliest record to the latest available at the time the search was conducted (May 2010). Medical Subject Headings, keywords and a pre-hospital search filter were used to yield relevant literature. Results: The search strategy yielded a total of 837 references. Seven hundred and fifty of these references were excluded as they did not meet the inclusion criteria. Of the 87 articles short listed for abstract or full-text review, six reported on ketamine use as an analgesic agent in the pre-hospital setting. Two papers were prospective randomized-controlled trials, and the number of patients included in the studies ranged from 4 to 164. Three studies aimed to report on the effectiveness of ketamine for pain intensity reduction; two concluded that ketamine provided safe and effective pain relief and one reported that ketamine reduced the amount of morphine required but was not associated with a reduction in pain intensity. One study identified a significantly higher prevalence of adverse effects following ketamine administration. The other studies reported no significant side effects and concluded that ketamine was safe. Conclusion: Ketamine is a safe and effective analgesic agent. The addition of ketamine as an analgesic agent may improve the management of patients presenting with acute traumatic pain in the pre-hospital setting.

Jeukendrup AE; Randell R. Fat burners: Nutrition supplements that increase fat metabolism. Obesity Reviews 12(10): 841-851, 2011. (82 refs.)

The term 'fat burner' is used to describe nutrition supplements that are claimed to acutely increase fat metabolism or energy expenditure, impair fat absorption, increase weight loss, increase fat oxidation during exercise, or somehow cause long-term adaptations that promote fat metabolism. Often, these supplements contain a number of ingredients, each with its own proposed mechanism of action and it is often claimed that the combination of these substances will have additive effects. The list of supplements that are claimed to increase or improve fat metabolism is long; the most popular supplements include caffeine, carnitine, green tea, conjugated linoleic acid, forskolin, chromium, kelp and fucoxanthin. In this review the evidence for some of these supplements is briefly summarized. Based on the available literature, caffeine and green tea have data to back up its fat metabolism-enhancing properties. For many other supplements, although some show some promise, evidence is lacking. The list of supplements is industry-driven and is likely to grow at a rate that is not matched by a similar increase in scientific underpinning.

Jumbelic MI. Deaths With transdermal fentanyl patches. American Journal of Forensic Medicine and Pathology 31(1): 18-21, 2010. (19 refs.)

Fentanyl is a potent Schedule II narcotic analgesic recommended for use in the management of unremitting pain not controlled by morphine or other opiate/opioid drugs. The danger inherent to fentanyl is its potency (greater than 50-100 times that of morphine) and rapidity of action, causing respiratory depression within minutes of administration. Advisories have been issued on a state and national level to health care providers and through manufacturers' package inserts for patients. Still, as will be demonstrated in this case review, the use of only a single transdermal patch taken as prescribed for the first time can prove fatal. A drug that requires such extensive warnings-that if unheeded lead to death because of its narrow therapeutic/toxic window, should have strict criteria and limited outpatient use. Initial medical observation and documentation for determining tolerance might be required before issuing a prescription. There has been a rise in the popularity of this drug evidenced by increased deaths among drug abusers and more prescriptions written. In the year 2006, the Center for Forensic Sciences in Onondaga County had 8 cases where fentanyl was considered the cause of death, often with other drugs detected in therapeutic concentrations. This number was a marked increase from the 1 to 2 cases occurring annually from 2002 to 2005. All of these 2006 overdoses because of fentanyl involved the transdermal formulation. The investigative data, blood and liver fentanyl levels, and autopsy findings will be presented.

Jungquist CR; Karan S; Perlis ML. Risk factors for opioid-induced excessive respriaratory depression. (review). Pain Management Nursing 12(3): 180-187, 2011. (54 refs.)

Opioid use has increased significantly over the past ten years and so has the incidence of reportable adverse events, such as respiratory depression and/or arrest. It is important for nurses to understand and know how to assess patients for risk factors for respiratory depression secondary to opioid therapy. This paper presents the pharmacodynamics of opioids, the risk factors for excessive respiratory depression, recommendations for identifying patients at high risk, and interventions to prevent adverse effects. After reading this paper, nurses will have the knowledge to provide safe administration of opioid medications for the management of acute pain.

American Society for Pain Management Nursing

Loftus RW; Yeager MP; Clark JA; Brown JR; Abdu WA; Sengupta DK et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 113(3): 639-646, 2010. (35 refs.)

Background: Ketamine is an N-methyl-D-aspartate receptor antagonist that has been shown to be useful in the reduction of acute postoperative pain and analgesic consumption in a variety of surgical interventions with variable routes of administration. Little is known regarding its efficacy in opiate-dependent patients with a history of chronic pain. We hypothesized that ketamine would reduce postoperative opiate consumption in this patient population. Methods: This was a randomized, prospective, double-blinded, and placebo-controlled trial involving opiate-dependent patients undergoing major lumbar spine surgery. Fifty-two patients in the treatment group were administered 0.5 mg/kg intravenous ketamine on induction of anesthesia, and a continuous infusion at 10 mu g kg(-1) min(-1) was begun on induction and terminated at wound closure. Fifty patients in the placebo group received saline of equivalent volume. Patients were observed for 48 h postoperatively and followed up at 6 weeks. The primary outcome was 48-h morphine consumption. Results: Total morphine consumption (morphine equivalents) was significantly reduced in the treatment group 48 h after the procedure. It was also reduced at 24 h and at 6 weeks. The average reported pain intensity was significantly reduced in the postanesthesia care unit and at 6 weeks. The groups had no differences in known ketamine-or opiate-related side effects. Conclusions: Intraoperative ketamine reduces opiate consumption in the 48-h postoperative period in opiate-dependent patients with chronic pain. Ketamine may also reduce opioid consumption and pain intensity throughout the postoperative period in this patient population. This benefit is without an increase in side effects.

Maani CV; DeSocio PA; Jansen RK; Merrell JD; McGhee LL; Young A et al. Use of ultra rapid opioid detoxification in the treatment of us military burn casualties. Journal of Trauma, Injury, Infection and Critical Care 71(supplement 1): S114-S119, 2011. (18 refs.)

Background: The purpose of this case series was to review the management of burn patients who requested ultrarapid opioid detoxification under anesthesia after extended duration of narcotic use for chronic pain related to burn injury. Methods: The treatment plan of six opioid-dependent burn patients was analyzed to assess the effectiveness of our detoxification practice to date. Demographic and clinical information was used to characterize the patient population served: age, burn size, injury severity, duration of narcotic use before detoxification intervention, and length of hospitalization stay. Daily narcotic consumption, in morphine equivalent units, was noted both before and after detoxification. Results: Six burn patients (average age, 31 years) underwent detoxification at the Burn Center during a hospitalization lasting between 1 day and 2 days. Average burn size was 38% total body surface area (range, 17-65); average Injury Severity Score was 30 (range, 25-38). Mean duration of narcotic use was 672 days (range, 239-1,156 days); average use of narcotics at time of detoxification was >200 units daily. Mean outpatient consumption for opioids after the intervention was minimal (<25 units/d). No complications were noted during any procedures. Conclusions: The results of ultrarapid opioid detoxification under anesthesia suggests that it is safe and effective for treating opioid addiction in military burn casualties when a coordinated, multidisciplinary approach is used. Safety and effectiveness to date validate current practice and supports incorporation into clinical practice guidelines. Further clinical research is warranted to identify those patients who may benefit most from detoxification and to determine the timing of such treatment.

Manchikanti L; Fellows B; Ailinani H; Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: A ten-year perspective. (review). Pain Physician 13(5): 401-435, 2010. (295 refs.)

The treatment of chronic pain, therapeutic opioid use and abuse, and the nonmedical use of prescription drugs have been topics of intense focus and debate. After the liberalization of laws governing opioid prescribing for the treatment of chronic non-cancer pain by state medical boards in the late 1990s, and with the introduction of new pain management standards implemented by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in 2000, opioids, in general, and the most potent forms of opioids including Schedule II drugs, in particular, have dramatically increased. Despite the escalating use and abuse of therapeutic opioids, nearly 15 to 20 years later the scientific evidence for the effectiveness of opioids for chronic non-cancer pain remains unclear. Concerns continue regarding efficacy; problematic physiologic effects such as hyperalgesia, hypogonadism and sexual dysfunction; and adverse side effects especially the potential for misuse and abuse and the increase in opioid-related deaths. Americans, constituting only 4.6% of the world's population, have been consuming 80% of the global opioid supply, and 99% of the global hydrocodone supply, as well as two-thirds of the world's illegal drugs. Retail sales of commonly used opioid medications (including methadone, oxycodone, fentanyl base, hydromorphone, hydrocodone, morphine, meperidine, and codeine) have increased from a total of 50.7 million grams in 1997 to 126.5 million grams in 2007. This is an overall increase of 149% with increases ranging from 222% for morphine, 280% for hydrocodone, 319% for hydromorphone, 525% for fentanyl base, 866% for oxycodone, to 1,293% for methadone. Average sales of opioids per person have increased from 74 milligrams in 1997 to 369 milligrams in 2007, a 402% increase. Surveys of nonprescription drug abuse, emergency department visits for prescription controlled drugs, unintentional deaths due to prescription controlled substances, therapeutic use of opioids, and opioid abuse have been steadily rising. This manuscript provides an updated 10-year perspective on therapeutic use, abuse, and nonmedical use of opioids and their consequences.

Marco EM; Garcia-Gutierrez MS; Bermudez-Silva FJ; Moreira FA; Guimaraes F; Manzanares J et al. Endocannabinoid system and psychiatry: In search of a neurobiological basis for detrimental and potential therapeutic effects. Frontiers in Behavioral Neuroscience 5: e-63, 2011

Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R) in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.

Marco EM; Garcia-Gutierrez MS; Bermudez-Silva FJ; Moreira FA; Guimaraes F; Manzanares J et al. Endocannabinoid system and psychiatry: In search of a neurobiological basis for detrimental and potential therapeutic effects. Frontiers in Behavioral Neuroscience 5: 63, 2011. (291 refs.)

Masterson GS; Hayes PC. Coffee and the liver: A potential treatment for liver disease? (review). European Journal of Gastroenterology & Hepatology 22(11): 1277-1283, 2010. (66 refs.)

Liver disease is the fifth commonest cause of death in the UK. Observational and case-controlled studies have suggested that coffee is beneficial in liver disease, but this evidence has yet to be evaluated or placed into the context of the natural history of liver disease. The aim of this study was to review the current evidence for the role of coffee in liver disease. Several studies consistently show that coffee drinkers have a reduced risk of abnormal liver function tests, cirrhosis and hepatocellular carcinoma. There is a clear dose response to this benefit. As the effect of this widely available food substance seems substantial further data, ideally from an interventional study of coffee in patients with liver disease, is urgently required particularly because of the potential to reduce fibrosis and hepatocellular carcinoma risk. This would be the first intervention of its kind to have proven benefit irrespective of etiology of liver disease.

Mathre ML. Cannabis as medicine: Why not? (editorial). Journal of Addictions Nursing 21(4): 171-173, 2010. (5 refs.)

McQuay HJ. More evidence cannabis can help in neuropathic pain. (editorial). Canadian Medical Association Journal 182(14): 1494-1495, 2010. (8 refs.)

Merza Z. Chronic use of opioids and the endocrine system. (review). Hormone and Metabolic Research 42(9): 621-626, 2010. (81 refs.)

Opioids are widely used for the management of acute and chronic pain. They are also abused for recreational purposes. Long term use may lead to abnormalities in the endocrine system. The axis mainly affected is the gonadal axis leading to hypogonadism. However adrenal insufficiency and growth hormone deficiency can also occur with evidence that other hormones are affected to a lesser extent. No large randomised controlled trials have been performed; however, evidence from several small studies on heroin addicts and chronic pain patients support the above. Hence it is important to consider hormonal abnormalities in patients on long term opioids and if suspected appropriate assessment would be warranted.

Mirken B. Medical marijuana policy catches up with science. Genetic Engineering & Biotechnology News 30(2): 6-7, 2010. (0 refs.)

Marijuana's recorded use as a medicine goes back nearly 5,000 years. The ban on such use is a much newer phenomenon-72 years in the U.S., a bit more or less in other nations and in specific U.S. states-and one whose unhappy tenure is now apparently near an end. Simply put, research has made that ban increasingly untenable. The two clearest signals of the sea change that is occurring came this past fall. In October, the Obama administration signaled a careful but hugely significant softening of the federal government's dogmatic hostility toward medical marijuana. Less than a month later, the American Medical Association (AMA) announced a reversal of its policy on the issue. The AMA's old language had urged that marijuana "be retained in Schedule I" of the federal Controlled Substances Act. That classification deemed marijuana as having a high potential for abuse, lacking accepted medical uses in the U.S., and as unsafe for use even under medical supervision. [In contrast, Schedule II-still considered to have high abuse potential but declared to have accepted medical uses and to be safe for use under physician supervision-includes cocaine, morphine, and even methamphetamine. Stranger still is the fact that in pill form, THC-the component responsible for marijuana's "high," though not all of its therapeutic effects-is in Schedule III, with controls so mild that phoned-in prescriptions are allowed.] A recent succession of controlled clinical trials has made the case irrefutable. The author reviews these clinical trials. A question of note is whether pharmaceutical companies will produce a synthetic cannabinoid medicine, better than Marinol currently available, and whether the government will push customers toward expensive pharmaceutical products, when many can get adequate and safe relief from a plant they can grow in their own backyard?

Myles TD. Steroids - plenty of benefits, but not without risk. (editorial). Obstetrics and Gynecology 117(2, Part 2 Supplement): 429-430, 2011. (13 refs.)

Nagarkatti M; Rieder SA; Hegde VL; Kanada S; Nagarkatti P. Do cannabinoids have a therapeutic role in transplantation? (review). Trends In Pharmacological Sciences 31(8): 345-350, 2010. (69 refs.)

Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties. Significant clinical and experimental data on the use of cannabinoids as anti-inflammatory agents exist in many autoimmune disease settings, but virtually no studies have been undertaken on their potential role in transplant rejection. Here we suggest a theoretical role for the use of cannabinoids in preventing allograft rejection. The psychotropic properties of CB1 agonists limit their clinical use, but CB2 agonists may offer a new avenue to selectively target immune cells involved in allograft rejection. Moreover, development of mixed CB1/CB2 agonists that cannot cross the blood brain barrier may help prevent their undesired psychotropic properties. In addition, manipulation of endocannabinoids in vivo by activating their biosynthesis and inhibiting cellular uptake and metabolism may offer another pathway to regulate immune response during allograft rejection.

Nicoletti A; Mostile G; Cappellani R; Contrafatto D; Arabia G; Lamberti P et al. Wine drinking and essential tremor: A possible protective role. Movement Disorders 26(7): 1310-1315, 2011. (34 refs.)

The purpose of this study was to evaluate the possible association of cigarette smoking, coffee drinking, and wine consumption with essential tremor using a matched case-control design. Cases and controls were enrolled from 6 Movement Disorder centers in central-southern Italy. Essential tremor was diagnosed according to Bain's criteria. Three unrelated healthy controls (not affected by neurological disorders) per each enrolled case, matched by sex and age (+/- 5 years), were selected. A standardized questionnaire was administered to record demographic, epidemiological, and clinical data. All cases and controls underwent a standard neurological examination. Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression for the matched cases and controls. Eighty-three patients with essential tremor (38 men and 45 women; mean age, 68.2 +/- 8.6 years) and 245 matched control subjects (113 men and 132 women; mean age, 68.4 +/- 9.7 years) were enrolled in the study. Multivariate analysis showed a significant negative association between essential tremor and wine consumption preceding the onset of disease (adjusted odds ratio, 0.23; 95% confidence interval, 0.08-0.64; P = .0005) with a significant dose effect (1-2 glass of wine per day: odds ratio, 0.32; 95% confidence interval, 0.10-0.95; P = .04; more than 3 glass of wine per day: odds ratio, 0.14; 95% confidence interval, 0.03-0.62; P = .01). In our sample no association between essential tremor and cigarette smoking or coffee drinking was found. Our data suggest a negative association between wine drinking and essential tremor, which could be explained by the long-term neuroprotective effect of its antioxidant components.

Nussbaum AM; Boyer JA; Kondrad EC. "But my doctor recommended pot": Medical marijuana and the patient-physician relationship. Journal of General Internal Medicine 26(11): 1364-1367, 2011. (16 refs.)

As the use of medical marijuana expands, it is important to consider its implications for the patient-physician relationship. In Colorado, a small cohort of physicians is recommending marijuana, with 15 physicians registering 49% of all medical marijuana patients and a single physician registering 10% of all patients. Together, they have registered more than 2% of the state to use medical marijuana in the last three years. We are concerned that this dramatic expansion is occurring in a setting rife with conflicts of interest despite insufficient scientific knowledge about marijuana. This system diminishes the patient-physician relationship to the recommendation of a single substance while unburdening physicians of their usual responsibilities to the welfare of their patients.

Obermannn M; Holle D. Hypnic headache. (review). Expert Review of Neurotherapeutics 10(9): 1391-1397, 2010. (44 refs.)

Hypnic headache is a rare primary headache disorder that is characterized by exclusively sleep-related headache attacks in patients usually beyond 50 years of age. Only 174 cases have been reported in the literature so far. Owing to its low prevalence, clinical features and therapeutic options, as well as underlying pathophysiologic mechanisms, are widely unknown or being controversially discussed. The association of hypnic headache with rapid-eye movement sleep was strongly contradicted in recent articles, while an association with hypothalamic dysfunction is thought to be one important pathophysiological mechanism. Common acute, as well as prophylactic, treatment is caffeine intake, either in the form of a cup of coffee or a caffeine tablet. Lithium, indomethacin and melatonin were promoted as potent medical treatments, while almost every other drug commonly used to treat headache or other pain syndromes was reported to be effective in single case reports on hypnic headache.

Peisah C; Chan DKY; McKay R; Kurrle SE; Reutens SG. Practical guidelines for the acute emergency sedation of the severely agitated older patient. Internal Medicine Journal 41(9): 651-657, 2011. (31 refs.)

The vulnerability of older people to serious underlying medical illness and adverse effects of psychotropics means that the safe and effective treatment of severe agitation can be lifesaving, the primary management goals being to create a safe environment for the patient and others, and to facilitate assessment and treatment. We review the literature on acute sedation and provide practical guidelines for the management of this problem addressing a range of issues, including aetiology, assessment, pharmacological and non-pharmacological strategies, restraint and consent. The assessment of the agitated older patient must include concurrent assessment of the likely aetiology of, the risks posed by, and the risks/benefits of management options for, the agitation. A range of environmental modifications and non-pharmacological strategies might be implemented to maximize the safety of the patient and others. Physical restraints should only be considered after appropriate assessment and trial of alternative management and if the risk of restraint is less than the risk of the behaviour. Limited evidence supports a range of pharmacological options from traditional antipsychotics to atypical antipsychotics and benzodiazepines. It is advised to start low and go slow, using small increments of dose increase. Medical staff are frequently called to sedate agitated older patients in hospital settings, often after hours, with limited access to relevant medical information and history. Safe and effective management necessitates adequate assessment of the aetiology of the agitation, exhausting all non-pharmacological strategies, and resorting to pharmacological and/or physical restraint only when necessary, judiciously and for a short-term period, with frequent review and the obtaining of consent as soon as possible.

Penido MG; Garra R; Sammartino M; Pereira e Silva Y. Remifentanil in neonatal intensive care and anaesthesia practice. (review). Acta Paediatrica 99(10): 1454-1463, 2010. (54 refs.)

Remifentanil is a relatively new ultrashort action synthetic opioid. Studies on the use of remifentanil in neonatology have emerged demonstrating its effectiveness and safety in neonates. The present study describes the use of remifentanil in both full-term and premature newborns, highlighting the theoretical benefits for this population in terms of both neonatal intensive care and anaesthesia. A Medline search was undertaken of all reviews and reports about the use of remifentanil in neonates published between 1996 and 2009 using MeSH search terms 'remifentanil', 'analgesia', 'anaesthesia', 'newborn' and 'neonate'. The review points that remifentanil has been used with advantages in newborns including preterm neonates and even for foetal anaesthesia. It proved to be a good option to attenuate the hemodynamic/endocrine markers of stress related to surgery. Owing to its unique pharmacokinetic profile, shorter extubation times can be achieved that makes the drug also a good option for short duration invasive procedures in NICUs (InSurE). A concern on its use is that the hemodynamic response (hypotension) may become significant when the drug is associated to other drugs like sevoflurane. Conclusion: Remifentanil seems to be an effective and safely used opioid for neonatal intensive care and anaesthesia practice.

Pollock AB; Tegeler ML; Morgan V; Baumrucker SJ. Morphine to methadone conversion: An interpretation of published data. American Journal of Hospice & Palliative Medicine 28(2): 135-140, 2011. (31 refs.)

For the past 20 years, methadone has been experiencing resurgence in the palliative care community as a second-line opioid for the treatment of cancer pain. The advantages of using methadone for refractory pain in patients with cancer or in those who could not tolerate the side effects of other opioids such as morphine are well cited in recent literature. Advantages of methadone over other opioids include dual elimination without active metabolites, allowing safe use with renal and liver failure, N-methyl-D-aspartate (NMDA) and delta receptor activity in addition to mu receptor agonism, multiple routes of administration, rapid onset of action, long half-life, low cost, and fewer adverse effects. Despite the abundance of recent case reports and literature reviews demonstrating the effective use of methadone in patients with cancer, there is a lack of consensus for an appropriate method for converting morphine (and by extension, other opioids) to methadone. This article will review methadone pharmacology and multiple proposed conversion methods; a case report illustrating a popular method for high-dose conversion is also included.

Power I. An update on analgesics. British Journal of Anaesthesia 107(1): 19-24, 2011. (51 refs.)

Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic efficacy/potency and reducing side-effect profile. This review article describes some of the recent advances with an emphasis on use in the acute setting. In this respect, opioids continue to be the mainstay (but not the only) analgesic and there have been important improvements in their clinical effect profile. For example, tapentadol has been introduced as a mixed opioid and norepinephrine uptake inhibitor which, unlike tramadol, does not require metabolic activation and does not suffer from isomer-dependent pharmacodynamics. Opioid antagonists have received much attention recently either used alone, methylnaltrexone (s.c) or alvimopan (p.o), or in combination, Targinact (oxycodone/naloxone), and appear to be effective in reducing opioid side-effects such as those in the gastrointestinal tract. Other agents where there has been recent development include the use of gabapentin, methylxanthines, and local anaesthetics. An interesting area of translation of basic research is in the inhibition of breakdown of endogenous opioids with opiorphin, targeting of the endocannabinoid system, and the use of ampakines to obtund opioid-induced side-effects. It is clear that there is still much work to be done, but the need for highly efficacious analgesics with good side-effect profile remains.

Reinarman C; Nunberg H; Lanthier F; Heddleston T. Who are medical marijuana patients? Population characteristics from nine California assessment clinics. Journal of Psychoactive Drugs 43(2): 128-135, 2011. (50 refs.)

Marijuana is a currently illegal psychoactive drug that many physicians believe has substantial therapeutic uses. The medical literature contains a growing number of studies on cannabinoids as well as case studies and anecdotal reports suggesting therapeutic potential. Fifteen states have passed medical marijuana laws, but little is known about the growing population of patients who use marijuana medicinally. This article reports on a sample of 1,746 patients from a network of nine medical marijuana evaluation clinics in California. Patients completed a standardized medical history form; evaluating physicians completed standardized evaluation forms. From this data we describe patient characteristics, self-reported presenting symptoms, physician evaluations, other treatments tried, other drug use, and medical marijuana use practices. Pain, insomnia, and anxiety were the most common conditions for which evaluating physicians recommended medical marijuana. Shifts in the medical marijuana patient population over time, the need for further research, and the issue of diversion are discussed.

Rintala DH; Fiess RN; Tan G; Holmes SA; Bruel BM. Effect of dronabinol on central neuropathic pain after spinal cord injury. American Journal of Physical Medicine & Rehabilitation 89(10): 840-848, 2010. (26 refs.)

Objective: To test the efficacy and safety of a cannabinoid, dronabinol, compared with an active control, diphenhydramine, in relieving neuropathic pain in persons with spinal cord injury. Design: A randomized, controlled, double-blind, crossover pilot study. Results: Seven adults with spinal cord injury and neuropathic pain below the level of injury participated. Two participants withdrew while receiving dronabinol, their first medication. For the remaining five participants, change in pain on a scale of 0-10 from baseline to the end of the maintenance phase did not differ significantly between the two medications (mean change, dronabinol: 0.20 +/- 0.837, range = -1.00 to 1.00; diphenhydramine: -1.80 +/- 2.490, range = -6.00 to 0; Wilcoxon Z = 1.63, P = 0.102). Similar results were found when the average of the two ratings during the maintenance phase was used (dronabinol: -0.20 +/- 0.671, range = -0.50 to 1.00; diphenhydramine: -1.40 +/- 1.245, range = -3.50 to -0.50; Wilcoxon Z = 1.60, P = 0.109). The most common side effects were dry mouth, constipation, fatigue, and drowsiness for both medications. Conclusions: On average, dronabinol was no more effective than diphenhydramine for relieving chronic neuropathic pain below the level of injury.

Sarne Y; Asaf F; Fishbein M; Gafni M; Keren O. The dual neuroprotective-neurotoxic profile of cannabinoid drugs. (review). British Journal of Pharmacology 163(7, special issue): 1391-1401, 2011. (137 refs.)

Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of Delta(9)-tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre- or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.

Schoedel KA; Chen N; Hilliard A; White L; Stott C; Russo E et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. Human Psychopharmacology: Clinical and Experimental 26(3): 224-236, 2011. (35 refs.)

Objective. This study aimed to evaluate the abuse potential and cognitive effects of nabiximols (Sativex (R), GW Pharma Ltd. Salisbury, UK), an oromucosal spray primarily containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Methods. This was a single-dose, randomized, double-blind, crossover study comparing nabiximols (4, 8, and 16 consecutive sprays: 10.8, 21.6, and 43.2 mg THC, respectively) with dronabinol 20 and 40 mg (synthetic THC: Marinol (R), Solvay Pharmaceuticals, Brussels, Belgium) and matching placebos in 23 recreational cannabis users. Subjective and cognitive/psychomotor measures were administered over 24 h post-dose. Results. Dronabinol was significantly different from placebo on abuse potential measures, thereby confirming study validity. Nabiximols 10.8 mg was not significantly different from placebo on primary measures but was different on some secondary measures. Nabiximols 21.6 mg was significantly greater than placebo on some primary/secondary measures, whereas nabiximols 43.2 mg showed significant effects on most measures. Nabiximols 10.8 mg was significantly lower than dronabinol doses on most measures (p < 0.05). Dronabinol 20 mg effects were numerically higher than nabiximols 21.6 mg but were statistically significant only for some measures. Dronabinol 40 mg and nabiximols 43.2 mg were generally not statistically different. Conclusions. Both dronabinol and nabiximols had significant abuse potential compared with placebo at higher doses. Nabiximols showed similar or slightly less abuse potential compared with dronabinol. Therefore, the abuse potential of nabiximols should be no higher than that of dronabinol.

Silva RR; Skimming JW; Muniz R. Cardiovascular safety of stimulant medications for pediatric attention-deficit hyperactivity disorder. Clinical Pediatrics 49(9): 840-851, 2010. (62 refs.)

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder that is often treated with stimulants such as methylphenidate and mixed amphetamine salts. Despite their efficacy and long history of use, there is concern about their potential for adverse cardiovascular effects in children and adolescents. Data from placebo-controlled and open-label extension trials published after 2000 were reviewed, and cardiovascular adverse event data were compared. Both placebo-controlled and open-label extension trials have repeatedly shown stimulant-induced increases in mean blood pressure, heart rate, and QT interval in children, adolescents, and adults. Although these increases seem relatively minor, their existence raises questions regarding whether stimulants could influence the likelihood of sudden death or other serious cardiovascular consequences, especially in patients with underlying heart problems. Moreover, questions have been raised regarding the necessity of screening patients for occult or unrecognized heart problems that are felt to be adversely affected by stimulant use. Obtaining a baseline electrocardiogram for any patient starting stimulant treatment is reasonable if access to such screening is readily available and not too costly.

Singh I; Kendall T; Taylor C; Mears A; Hollis C; Batty M et al. Young people's experience of ADHD and stimulant medication: A qualitative study for the NICE Guideline. Child and Adolescent Mental Health 15(4): 186-192, 2010. (18 refs.)

Background: The NICE ADHD Guideline Group found a lack of research evidence on young people's experiences with stimulant medications. The present study was commissioned to help fill this gap in the evidence base and to inform the Guideline. Method: Focus groups and 1: 1 interviews with 16 UK young people with ADHD. Results: Young people were positive about taking medication, feeling that it reduced their disruptive behaviour and improved their peer relationships. Young people experienced stigma but this was related more to their symptomatic behaviours than to stimulant drug medication. Conclusions: The study's findings helped to inform the NICE guideline on ADHD by providing evidence that young people's experiences of medication were in general more positive than negative. All NICE Guidelines involving recommendations for the treatment of young people should draw on research evidence of young people's experiences of treatments.

Swartz R. Medical marijuana users in substance abuse treatment. Harm Reduction Journal 7: article 2, 2010. (34 refs.)

Background: The rise of authorized marijuana use in the U. S. means that many individuals are using cannabis as they concurrently engage in other forms of treatment, such as substance abuse counseling and psychotherapy. Clinical and legal decisions may be influenced by findings that suggest marijuana use during treatment serves as an obstacle to treatment success, compromises treatment integrity, or increases the prevalence or severity of relapse. In this paper, the author reviews the relationship between authorized marijuana use and substance abuse treatment utilizing data from a preliminary pilot study that, for the first time, uses a systematic methodology to collect data examining possible effects on treatment. Methods: Data from the California Outcomes Measurement System (CalOMS) were compared for medical (authorized) marijuana users and non-marijuana users who were admitted to a public substance abuse treatment program in California. Behavioral and social treatment outcomes recorded by clinical staff at discharge and reported to the California Department of Alcohol and Drug Programs were assessed for both groups, which included a sample of 18 reported medical marijuana users. Results: While the findings described here are preliminary and very limited due to the small sample size, the study demonstrates that questions about the relationship between medical marijuana use and involvement in drug treatment can be systematically evaluated. In this small sample, cannabis use did not seem to compromise substance abuse treatment amongst the medical marijuana using group, who (based on these preliminary data) fared equal to or better than non-medical marijuana users in several important outcome categories (e. g., treatment completion, criminal justice involvement, medical concerns). Conclusions: This exploratory study suggests that medical marijuana is consistent with participation in other forms of drug treatment and may not adversely affect positive treatment outcomes. These findings call for more extensive sampling in future research to allow for more rigorous research on the growing population of medical marijuana users and non-marijuana users who are engaged in substance abuse treatment.

Tanasescu R; Rog D; Constantinescu CS. A drug discovery case history of 'delta-9-tetrahydrocannabinol, cannabidiol,' (review). Expert Opinion on Drug Discovery 6(4): 437-452, 2011. (129 refs.)

Introduction: Although the Cannabis sativa herb has been known for its therapeutic benefit for centuries, the interest in the clinical potential of cannabinoid-based drugs escalated after the discovery of the endocannabinoid system. The understanding of their actions at the molecular level indicates that the therapeutic applications of cannabinoids (plant-derived or synthetic) may be diverse. Several drugs containing cannabinoids are currently used in the therapy of emesis, pain and spasticity. Areas covered: This drug discovery case history reviews the preclinical and clinical development of Sativex (R) ('delta-9-tetrahydrocannabinol, cannabidiol'; nabiximols). Sativex is the first licensed phytocannabinoid-based drug approved, or in the process of approval, as therapy for indications such as MS-associated spasticity or chronic pain. Sativex contains a combination of two cannabinoids in approximately equal quantities (delta-9-tetrahydrocannabinol and cannabidiol) and is administered via an oromucosal pump spray, aiming at minimising psychotropic side effects and first pass effect. Pivotal clinical safety and efficacy data that led to Sativex's approval are discussed, as well as issues that have arisen with its clinical usage. Expert opinion: Although pleiotrophic effects of cannabinoids may raise complex issues beyond their symptomatic effects, standardised pharmaceutical cannabinoids may constitute a useful addition to the pharmacotherapeutic armamentarium in chronic conditions insufficiently alleviated by existing drugs.

Tremblay J; Hamet P. Genetics of pain, opioids, and opioid responsiveness. Metabolism, Clinical and Experimental 59(Supplement 1): S5-S8, 2010. (24 refs.)

Pain is an integral part of the defense mechanisms required for survival. Several hereditary syndromes of complete or almost complete insensitivity to pain have been identified and include channelopathy-associated pain insensitivity, of which the most likely candidate gene is the a-subunit of the voltage-gated sodium channel known as Na(v)1.7. Five hereditary sensory and autonomic neuropathy syndromes have been described. Variable pain sensitivity in the general population has been linked to common variants of the mu-opioid receptor and of the catecholamine-O-methyltransferase genes potentially leading to increased opioid tonus. Variants of the guanosine triphosphate cyclohydrolase 1/dopa-responsive dystonia gene appear to regulate nociception. Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1, gene and the melanocortin-1 receptor gene. Candidate genes for predicting opioid efficacy are drug-metabolizing enzymes and transporters-including cytochrome P450, uridine 5'-diphosphate-glucuronosyltransferases, and adenosine triphosphate-binding cassette transporters-that are involved in opioid metabolism. Most current knowledge on the genetic regulation of pain has been derived from animal models developed mainly in mice. Genomics has the potential to contribute to therapeutic advances with the promising approach of using small interfering RNA in the control of neuropathic pain. Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles.

Tucker LM. High stakes: How to define "disability" in medical marijuana states in light of the Americans with Disabilities Act, Canadian law, and the impact on employers. Indiana International & Comparative Law Review 21: 359, 2011. (359 legal refs.)

... Neither our northern neighbor's position nor a minority of states' medical marijuana laws should make the rest of the United States second guess the legality of disability discrimination laws. ... The employer asserted the following defenses: 1 Oregon's Medical Marijuana Law does not require employers to accommodate the use of medical marijuana in the workplace or to accommodate off-duty use of medical marijuana in such a fashion that the employee would or could still be affected by such usage while on duty. 2 Employer is not required to accommodate medical marijuana users by permitting them to work in safety-sensitive positions that would or could endanger the safety of themselves, co-workers or the public. 3 Employer is free to require that employees behave in conformance with the Federal Drug-Free Workplace Act of 1988. ... It is triggered when an employees sic is suffering from an addiction which requires accommodation or treatment." ... These tools to help implement and enforce drug-free workplaces include drug policies, employee drug testing, and other resources from occupational safety and health administrations. ... States Should Protect Employers' Rights States should protect an employer's right to enforce a drug-free workplace through a variety of measures, such as cautiously drafting medical marijuana acts, passing bills to amend existing acts to clarify that employers have no duty to accommodate medical marijuana use, and ensuring that courts continue interpreting medical marijuana laws with an eye toward decriminalization.

Vollenweider FX; Kometer M. OPINION. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. (review). Nature Reviews. Neuroscience 11(9): 642-651, 2010. (149 refs.)

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

Wall MM; Poh E; Cerda M; Keyes KM; Galea S; Hasin DS. Adolescent marijuana use from 2002 to 2008: Higher in states with medical marijuana laws, cause still unclear. Annals of Epidemiology 21(9): 714-716, 2011. (10 refs.)

PURPOSE: Since 1996, 16 states have legalized marijuana use for medical purposes. The current study provides a scientific assessment of the association of medical marijuana laws (MML) and adolescent marijuana use using national data. METHOD: State representative survey data on approximately 23,000 12-17 year olds were collected by the National Survey on Drug, Use and Health annually from 2002-2008. Yearly state-specific estimates of prevalence of past-month marijuana use and perception of its riskiness were statistically tested for differences between states with and without MML by year and across years. RESULTS: States with MML had higher average adolescent marijuana use, 8.68% (95% Cl: 7.95-9.42) and lower perception of riskiness, during the period 2002-2008 compared to states without MML, 6.94% (95% Cl: 6.60-7.28%). In the eight states that passed MML since 2004, in the years prior to MML passage, there Was already a higher prevalence of use and lower perceptions of risk in those states compared to states that have not passed MML. CONCLUSIONS: While the most likely of several possible explanations for higher adolescent marijuana use and lower perceptions of risk in MML states cannot be determined from the current study, results clearly suggest the need for more empirically-based research on this topic.

Wang GS; Narang SK; Wells K; Chuang R. A case series of marijuana exposures in pediatric patients less than 5 years of age. Child Abuse & Neglect 35(7): 563-565, 2011. (6 refs.)

This is a retrospective case series of marijuana exposures that have presented to the emergency department (ED) in children less than 6 years of age. A total of 5 patients were identified between November 2009 through March 2010. The age range was 10 months to 4 years, all were male. They all presented to the ED with abnormal neurologic physical exams consisting of lethargy and somnolence. One patient also had bradycardia. All the patients had extensive laboratory and radiographic work ups in the ED; ultimately, the urine toxicology screen confirmed THC ingestions in all the patients. Two patients were admitted, 1 to the intensive care unit ; the remaining 3 were observed in the emergency department . It was determined that 4 of the 5 patients had household members with confirmed medical marijuana cards, and these children were explosed to medical marijuana. Exposures in such young patients may be from ingestion, passive inhalation or both. Prior case reports have demonstrated significant symptoms from ingestions, including coma resulting from airway obstruction though there have been no reported fatalities to poison control centers from exposures solely from marijuana, this case series highlights the significant morbidity of this increasing environmental exposure to marijuana in children.

Ware MA. Clearing the smoke around medical marijuana. (editorial). Clinical Pharmacology & Therapeutics 90(6): 769-771, 2011. (10 refs.)

The hazy world of "medical marijuana" continues to cry out for clear data on which to base medical decision making and rational policy design. In this issue of Clinical Pharmacology & Therapeutics, Abrams and colleagues report that vaporized cannabis does not meaningfully affect opioid plasma levels and may even augment the efficacy of oxycodone and morphine in patients with chronic non-cancer pain. This Commentary considers the implications of this work for clinical practice and further research initiatives.

Welsh EJ; Bara A; Barley E; Cates CJ. Caffeine for asthma. (review). Cochrane Database of Systematic Reviews 1: CD001112, 2010. (20 refs.)

Background: Caffeine has a variety of pharmacological effects; it is a weak bronchodilator and it also reduces respiratory muscle fatigue. It is chemically related to the drug theophylline which is used to treat asthma. It has been suggested that caffeine may reduce asthma symptoms and interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in asthma, this is the first review to systematically examine and summarise the evidence. Objectives: To assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to either lung function or exhaled nitric oxide testing. Search strategy We searched the Cochrane Airways Group trials register and the reference lists of articles (August 2009). We also contacted study authors. Selection criteria: Randomised clinical trials of oral caffeine compared to placebo or coffee compared to decaffeinated coffee in adults with asthma. Data collection and analysis Trial selection, quality assessment and data extraction were done independently by two reviewers. Main results: Seven trials involving a total of 75 people with mild to moderate asthma were included. The studies were all of cross-over design. Six trials involving 55 people showed that in comparison with placebo, caffeine, even at a 'low dose' (< 5 mg/kg body weight), appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one minute showed a small improvement up to two hours after caffeine ingestion (SMD 0.72; 95% CI 0.25 to 1.20), which translates into a 5% mean difference in FEV1. However in two studies the mean differences in FEV1 were 12% and 18% after caffeine. Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours. One trial involving 20 people examined the effect of drinking coffee versus a decaffeinated variety on the exhaled nitric oxide levels in patients with asthma and concluded that there was no significant effect on this outcome. Authors' conclusions: Caffeine appears to improve airways function modestly, for up to four hours, in people with asthma. People may need to avoid caffeine for at least four hours prior to lung function testing, as caffeine ingestion could cause misinterpretation of the results. Drinking caffeinated coffee before taking exhaled nitric oxide measurements does not appear to affect the results of the test, but more studies are needed to confirm this.

Yagoubian B; Akkara J; Afzali P; Alfi DM; Olson L; Conell-Price J et al. Nicotine nasal spray as an adjuvant analgesic for third molar surgery. Journal of Oral and Maxillofacial Surgery 69(5): 1316- 1319, 2011. (14 refs.)

Purpose: To determine the efficacy of preoperatively administered nicotine nasal spray (3 mg) for analgesia after third molar (TM) surgery. Materials and Methods: A single-center, prospective, randomized, double-blind, crossover trial was conducted. The study population consisted of 20 nonsmoking patients referred to the Department of Oral and Maxillofacial Surgery of Columbia University College of Dental Medicine for extraction of all 4 TMs. Each patient received nicotine nasal spray or placebo spray before TM surgery. At a subsequent visit the contralateral TMs were removed with prior administration of the alternate treatment. For an hour postoperatively, subjects reported information on pain and nausea, and hemodynamic variables were recorded at 15-minute intervals. Telephone follow-up was recorded for 5 days postoperatively, where patients reported information on pain, nausea, and use of hydrocodone/acetaminophen as rescue analgesia. Results: Nicotine treatment was associated with a highly significant decrease in pain reported during the 5 days after TM surgery. There was no difference in the amount of hydrocodone/acetaminophen used or amount of nausea reported. There was a small but significant increase in heart rate after nicotine treatment compared with placebo during the first hour after surgery. There was no difference in blood pressure between groups. Conclusion: Pain is well controlled by hydrocodone/acetaminophen in most patients after TM surgery. However, there is significant variability in pain reported. Nicotinic agonists represent a new class of analgesic that can be considered for patients who are expected to have significant opioid-resistant pain after TM surgery. Caution should be used with patients in whom a small increase in heart rate would be deleterious.

Younger JW; Chu LF; D'Arcy NT; Trott KE; Jastrzab LE; Mackey SC. Prescription opioid analgesics rapidly change the human brain. Pain 152(8): 1803-1810, 2011. (58 refs.)

Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward-and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.