Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs.

Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Improved Treatment Effect of Triamcinolone Acetonide Extended-Release in Patients with Concordant Baseline Pain Scores on the Average Daily Pain and Western Ontario and McMaster Universities Osteoarthritis Index Pain Scales.

INTRODUCTION: A phase 3 randomized controlled study comparing triamcinolone acetonide extended-release (TA-ER) to conventional TA crystalline suspension (TAcs) reported variable efficacy results. Enrollment criteria may have contributed to this discrepancy, as moderate-to-severe average daily pain (ADP) was required at baseline, whereas no limitations were placed on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A) pain severity. We conducted a post hoc sensitivity analysis to compare treatment effects in patients reporting moderate-to-severe osteoarthritis (OA) pain on both scales. METHODS: Participants > 40 years old with symptomatic knee OA were randomly assigned to a single intra-articular injection of TA-ER 32 mg, TAcs 40 mg, or saline-placebo and followed for 24 weeks. Patient-reported ADP, WOMAC-A, rescue medication usage, and adverse events (AEs) were assessed. Participants who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥ 5 to ≤ 9, maximum 10 and WOMAC-A ≥ 2, maximum 4) were categorized as "concordant" pain reporters; patients with baseline moderate-to-severe OA on ADP only were termed "discordant" pain reporters. RESULTS: Two-hundred-ninety-two concordant pain reporters of 484 total subjects received TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or saline-placebo (n = 97). Baseline characteristics and AE profiles of the concordant and discordant pain responders were consistent with the full analysis population. Among concordant pain reporters, TA-ER significantly (p < 0.05) improved ADP scores vs. TAcs (weeks 5-19; area-under-the-effect [AUE]weeks1-12; AUEweeks1-24) and saline-placebo (weeks 1-20; AUEweeks1-12; AUEweeks1-24). At week 12, a higher proportion reported no knee pain (ADP = 0) with TA-ER (~ 28%) vs. TAcs (~ 8%). TA-ER significantly improved WOMAC-A vs. TAcs at weeks 4, 8, and 12, with significant reduction in rescue medication usage observed with TA-ER from weeks 2 to 20 vs. TAcs. CONCLUSIONS: In patients reporting moderate-to-severe knee OA pain at baseline based on concordant ADP and WOMAC-A scores, TA-ER provided statistically significant pain relief for ≥ 12 weeks compared with conventional TAcs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357459.

Osteoarthritis is a chronic condition that greatly impacts patients. Pain is the most common symptom of osteoarthritis. Clinical trials evaluating the effects of new drugs to treat osteoarthritis pain frequently use scales to rate overall pain following treatment. Patients may rate their pain using a number that best describes their pain, with the lowest number typically meaning "no pain," and the highest number typically meaning "pain as bad as you can imagine." Other rating scales may be used to rate pain in situations commonly associated with osteoarthritis.Results from a large clinical trial demonstrated that injection of an extended-release steroid significantly reduced pain compared with a conventional steroid injection on only one of the two pain-reporting scales used in the trial. A closer look found that some patients reported their pain differently on the two rating scales at the start of the trial, with some reporting moderate-to-severe pain using one questionnaire and mild pain using the other. Here, we focused on those patients who reported having moderate-to-severe osteoarthritis knee pain on both pain scales at the start and found that the pain relief benefit associated with the extended-release steroid injection was greatly improved compared with the conventional steroid injection with both measures. Patients receiving the extended-release steroid injection also decreased their use of rescue medication for pain relief.

Short-acting and Long-acting Opioids Utilization among Women Diagnosed with Endometriosis in the United States: A Population-based Claims Study.

STUDY OBJECTIVE: To determine the prevalence and pattern of opioid use in endometriosis and the characteristics of patients prescribed an opioid using medical insurance claims data. DESIGN: We performed a retrospective cohort analysis of data from the Truven MarketScan Commercial database for the period of January 1, 2011 to December 31, 2016. SETTING: The Truven database includes inpatient, outpatient, and prescription claims covering more than 115 million unique individuals and over 36 million inpatient hospital discharges across multiple payer types and all 50 states. PATIENTS: Women with endometriosis were defined as those with 1 inpatient or 2 outpatient codes for endometriosis. INTERVENTIONS: No interventions were assigned. Women who filled an opioid prescription within 12 months of diagnosis were placed in the opioid cohort and women who did not fill an opioid prescription were placed in the nonopioid cohort. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were evaluated 12 months preindex (date of the first diagnosis) and opioid use was assessed for 12 months after the index date. The dataset included 58 472 women with endometriosis. Of these, 61.7% filled an opioid prescription during the study period. More than 95% filled prescriptions for short-acting opioids (SAOs) only, 4.1% filled prescriptions for both SAOs and extended-release/long-acting opioids (LAOs), and 0.6% filled prescriptions for LAOs only. Patients who filled an opioid prescription had higher baseline comorbidities (especially gynecologic and chronic pain comorbidities) and endometriosis-related medication use compared with patients who did not fill an opioid prescription during the study period. Patients who filled both LAO and SAO prescriptions had the highest total days' supply of opioids, the proportion of days covered by prescriptions, and morphine equivalent daily dose. These patients also had the highest proportions of opioid switching and dose augmentation. Statistical trends in data were not substantially altered when analyses excluded patients with chronic pain comorbidities or surgical opioid prescriptions. CONCLUSION: Although opioids are not a recommended treatment for endometriosis, more than half of our cohort filled an opioid prescription within 1 year after a first recorded diagnosis of endometriosis. Patients who filled an opioid prescription tended to use more endometriosis-related medications and have a higher comorbidity burden. Additional research is necessary to better understand the reasons and outcomes associated with opioid utilization in endometriosis and to determine if there is a more effective pain management treatment plan for patients taking opioids.

Placebo Response Reduction and Accurate Pain Reporting Training Reduces Placebo Responses in a Clinical Trial on Chronic Low Back Pain: Results From a Comparison to the Literature.

OBJECTIVE: A literature review was conducted to compare placebo responses in a recent trial-which implemented an accurate pain reporting (APR) and placebo response reduction (PRR) training program-with placebo responses in similar previous trials in chronic lower back pain (CLBP) that did not use such training. METHODS: A literature search was performed to find parallel design, randomized, controlled trials of pharmacological treatments administered orally or through intravenous injection for CLBP. Studies were assessed for the proportion of placebo responders, defined as the proportion of patients in the placebo group with ≥30% reduction in pain intensity. A χ analysis was performed on the proportion of responders from the SPRINT trial and from other similar studies. RESULTS: Of 844 studies identified in the initial screening process, 16 studies were included for comparison. The percentage of placebo responders was statistically significantly lower in the SPRINT study (19.1%) compared with other CLBP trials (38.0%) (P=0.003). Our results show that the placebo response was lower in the SPRINT trial than other comparable studies on CLBP. DISCUSSION: These findings are consistent with results from other studies showing that neutralizing subject and study staff expectations of therapeutic benefit can decrease the placebo response in clinical trials. The results of this study suggest training participants and staff to improve pain reporting accuracy, neutralize expectations, and decrease external cues that may bias participants' pain ratings in clinical trials may effectively decrease the placebo response leading to increased assay sensitivity.

Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic, using the MADDERS® system (Misuse, Abuse, and Diversion Drug Event Reporting System).

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12 weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo. System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest.Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to "Withdrawal" and, primarily in SUMMIT-07, "Therapeutic Error" (unintentional overuse) or "Misuse" (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible "Abuse" events (three NKTR-181, two placebo) in SUMMIT-07 and four possible "Abuse" events (all NKTR-181) in SUMMIT-LTS.Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.

A deeper look at pain variability and its relationship with the placebo response: results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee.

Previous studies have shown a robust correlation between variability of clinical pain scores and responsiveness to placebo (but not active drug) in pain studies, but explanations for these relationships are lacking. We investigated this further by assessing relationship between the Focused Analgesia Selection Test (FAST), a psychophysical method that quantifies pain reporting variability in response to experimental stimuli, variability of daily clinical pain scores as captured using diary, and response to treatment in the context of a randomized controlled crossover trial of naproxen vs placebo in knee osteoarthritis. Evoked pain using the Staircase-Evoked Pain Procedure served as the primary efficacy endpoint. Variability of daily pain scores and the FAST were assessed at baseline. Fifty-five subjects completed the study and were included in the analyses. Our results indicated a statistically significant, moderate linear relationship between variability of clinical and experimental pain reports (r = -0.416, P = 0.004). Both correlated with the placebo response (r = 0.393, P = 0.004; r =-0.371, P = 0.009; respectively), but only the FAST predicted the treatment difference between naproxen and placebo, as demonstrated both in a regression model (P = 0.002, Beta = 0.456, t = 3.342) and in a receiver operating characteristic curve (0.721) analysis. Our results extend previous findings to include a correlation between experimental pain variability and the placebo response and suggest that experimental pain variability is a better predictor of patients who respond preferentially to drug over placebo. A theoretical model unifying these observations is proposed, and practical implications are discussed.

Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents.

Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.

Anatabine supplementation decreases thyroglobulin antibodies in patients with chronic lymphocytic autoimmune (Hashimoto's) thyroiditis: a randomized controlled clinical trial.

CONTEXT: Hashimoto's thyroiditis is less prevalent in tobacco smokers. Anatabine, an alkaloid found in Solanaceae plants including tobacco, has been reported to ameliorate a mouse model of Hashimoto's thyroiditis. OBJECTIVE: The effects of anatabine in patients with Hashimoto's thyroiditis were studied. DESIGN, SETTING, PATIENTS, AND INTERVENTION: This was a double-blind, randomized, placebo-controlled multisite study. A total of 146 patients (70 treated with anatabine and 76 with placebo) completed the study. Approximately 50% of patients in each group were taking levothyroxine. Anatabine lozenges (9-24 mg/d) or placebo, each containing vitamins A and D3, were administered orally 3 times a day for 3 months. MAIN OUTCOME MEASURES: Serum thyroperoxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels were assessed. Safety was assessed through adverse events, clinical laboratory evaluations, and vital sign measurements. RESULTS: Anatabine-treated patients had a significant reduction in absolute serum TgAb levels from baseline by study end relative to those receiving placebo (P=.027); however, there were no significant changes or differences in treatment group means for TPOAb or TgAb levels. Mean±SD TgAb values decreased by 46.2±101.1 and 3.9±83.9 World Health Organization units for the anatabine and placebo groups, respectively. Significantly more patients had a >20% drop in TgAb levels in the anatabine than placebo group (P=.023). Overall, the anatabine supplement was safe and well tolerated, although significantly (P<.05) more patients in the anatabine group reported adverse events. CONCLUSIONS: These results demonstrate an immunological effect of anatabine on TgAb levels. Further studies are warranted to determine the longer-term effects and possible actions of anatabine on the course of Hashimoto's thyroiditis.

Effects of a facial cream containing the minor alkaloid anatabine on improving the appearance of the skin in mild to moderate rosacea: an open-label case series study.

BACKGROUND: Current medical and scientific research indicates that rosacea, a chronic and often debilitating skin condition that primarily affects the central face, may be caused by an overactive or excessive inflammatory immune response. Regardless of etiology, the accompanying redness and inflammation is unsightly and difficult for the patient. Anatabine is an alkaloid from the plant family Solanaceae that has been shown in several preclinical studies to modulate proinflammatory signaling pathways. OBJECTIVE: A cream containing anatabine was developed and evaluated in an open-label case series study for safety and effects on the appearance of the skin in 10 patients with mild to moderate rosacea. METHODS: Patients applied the cream to the face twice daily for a period of 30 days. Patients and the study physician completed safety and efficacy assessments at study end. RESULTS: Results showed that 50% of the patients self-reported improvement in the appearance of their skin, and the physician noted improvement in 70% of the patients. Photographs taken before and after 30 days of cream use provide visual evidence of the improvement in several patients. There were no complications or adverse events reported by any of the patients in the study, indicating that the anatabine cream was safe and very well tolerated. CONCLUSION: The results of this open-label case series show that a facial cream containing anatabine can improve the appearance of the skin in patients with mild to moderate rosacea and suggest that a double-blind, vehicle-controlled trial in a larger number of subjects is warranted.

Effects of dietary supplementation with the solanaceae plant alkaloid anatabine on joint pain and stiffness: results from an internet-based survey study.

Anatabine is a Solanaceae plant family alkaloid marketed in the United States as a dietary supplement. It has demonstrated anti-inflammatory effects in vivo and in vitro, and may be useful for musculoskeletal aches and pains. The purpose of this internet-based survey study was to provide more information about anatabine users who report benefits for joint pain or stiffness. Of the 282 survey respondents, 232 (82%) reported a benefit from anatabine supplementation for one or more joint pain conditions, most commonly the knee, wrists/hands/fingers, shoulder, and back, most often due to osteoarthritis or injury to the joint. Mean scores of joint pain and stiffness were significantly (P < 0.0001) reduced after starting anatabine supplementation, and for most respondents joint pain was virtually eliminated. Around 90% of all individuals rated the effect of anatabine supplementation as good or excellent for joint pain, stiffness, functionality, and overall effects. These results provide evidence that anatabine supplementation can lead to substantial improvement of musculoskeletal aches, pains, and stiffness, and can provide benefits in some individuals for various medical conditions in multiple joint locations.

Discriminative stimulus effects of tramadol in humans.

Tramadol is an unscheduled atypical analgesic that acts as an agonist at µ-opioid receptors and inhibits monoamine reuptake. Tramadol can suppress opioid withdrawal, and chronic administration can produce opioid physical dependence; however, diversion and abuse of tramadol is low. The present study further characterized tramadol in a three-choice discrimination procedure. Nondependent volunteers with active stimulant and opioid use (n = 8) participated in this residential laboratory study. Subjects were trained to discriminate between placebo, hydromorphone (8 mg), and methylphenidate (60 mg), and tests of acquisition confirmed that all volunteers could discriminate between the training drugs. The following drug conditions were then tested during discrimination test sessions: placebo, hydromorphone (4 and 8 mg), methylphenidate (30 and 60 mg), and tramadol (50, 100, 200, and 400 mg). In addition to discrimination measures, which included discrete choice, point distribution, and operant responding, subjective and physiological effects were measured for each test condition. Both doses of hydromorphone and methylphenidate were identified as hydromorphone- and methylphenidate-like, respectively. Lower doses of tramadol were generally identified as placebo, with higher doses (200 and 400 mg) identified as hydromorphone, or opioid-like. The highest dose of tramadol increased ratings on the stimulant scale, but was not significantly identified as methylphenidate-like. Tramadol did not significantly increase subjective ratings associated with reinforcement. Taken together, these results extend previous work with tramadol as a potential medication for the treatment of opioid dependence and withdrawal, showing acute doses of tramadol exhibit a profile of effects similar to opioid agonists and may have abuse liability in certain populations.

Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers.

STUDY OBJECTIVE: To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg. DESIGN: Open-label, randomized, single-dose, 4-treatment crossover study. SETTING: Clinical research unit. PATIENTS: 30 healthy, ASA physical status I adult men. INTERVENTIONS: Subjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7. MEASUREMENTS: Platelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC(0-6h)). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time. MAIN RESULTS: AUC(0-6h) (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events. CONCLUSIONS: Acetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.

Physical dependence potential of daily tramadol dosing in humans.

RATIONALE: Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. OBJECTIVES: The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. METHODS: Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. RESULTS: Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. CONCLUSIONS: Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Effects of repeated tramadol and morphine administration on psychomotor and cognitive performance in opioid-dependent volunteers.

Tramadol is an atypical, mixed mechanism analgesic used to treat moderate to severe pain. Based on evidence that tramadol has relatively low abuse potential and can relieve opioid withdrawal, tramadol may be useful for treating opioid dependence. The purpose of this study was to assess the performance side-effect profile of tramadol. Nine opioid-dependent volunteers completed a performance battery following 5-7 days of subcutaneous morphine (15 mg, 4 times/day) and two doses of oral tramadol (50, 200 mg, 4 times/day) in a within subject cross-over design. Morphine was always the first condition, and the order of the two tramadol doses was randomized and double blind. Performance was significantly worse in the morphine condition relative to one or both tramadol doses on measures of psychomotor speed/coordination (circular lights task), psychomotor speed/pattern recognition (DSST speed measure) and psychomotor speed/set shifting (trail-making tasks). There were no significant differences among conditions in DSST accuracy, simple reaction time, divided attention, working memory, episodic memory, metamemory, or time estimation. Neither tramadol dose was associated with worse performance than morphine on any measure. Although practice sessions were conducted prior to the first session to reduce order effects, the possibility that residual practice effects contributed to the differences between tramadol and morphine cannot be ruled out. The high tramadol dose produced worse performance than the low dose only on the balance measure. These findings suggest that tramadol is generally a safe medication with respect to cognitive and psychomotor measures and support tramadol's further evaluation as an opioid-dependence treatment.

Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

RATIONALE: Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. OBJECTIVE: Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. MATERIALS AND METHODS: This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. RESULTS: The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. CONCLUSIONS: The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

Opioid detoxification via single 7-day application of a buprenorphine transdermal patch: an open-label evaluation.

RATIONALE: Managed withdrawal (i.e., detoxification) from opioid dependence is a widespread clinical procedure that is a necessary step for those pursuing abstinence. Buprenorphine is one effective detoxification treatment, however, consensus regarding effective detoxification procedures is lacking. OBJECTIVES: This study evaluated the efficacy of a buprenorphine transdermal formulation (i.e., patch) in suppressing opioid withdrawal, its safety and tolerability, and its biodelivery when applied for 7 days. METHODS: Physically dependent opioid (heroin) users (n = 12) completed a 10-day opioid detoxification in a residential research unit. Each received a single patch application that remained in place for 7 days. Blood samples were drawn prior to patch application and once daily thereafter. Assessments, four times daily, included: the amount of rescue medications ordered to treat withdrawal discomfort; self-report and observer ratings of opioid withdrawal and agonist effects; and vital sign measures. RESULTS: Overall, the patch appeared safe and well-tolerated. Buprenorphine plasma levels peaked 48 h after patch application at 0.59 ng/ml. Indices of withdrawal (self-reports, observer ratings, rescue medication) were significantly reduced within 24 h of patch application, continued to decline thereafter, and did not reappear following patch removal. CONCLUSIONS: This study confirms that transdermal buprenorphine is safe and clinically effective, and suggests that a 7-day application may provide an effective and comfortable means of detoxification. This patch formulation would appear to be a useful opioid detoxification treatment by reducing compliance concerns, and administering buprenorphine in a formulation less likely to be diverted to illicit use.

Evaluation of a transdermal buprenorphine formulation in opioid detoxification.

AIMS: Buprenorphine is marketed in a sublingual formulation for treatment of opioid dependence. A transdermal formulation has been developed that may provide extended relief from opioid withdrawal, reduce required clinic visits and improve adherence, while having less potential for diversion and abuse. This study evaluated the safety and biodelivery (blood levels) of this transdermal buprenorphine formulation (i.e. buprenorphine patch), and its apparent efficacy in suppressing the opioid withdrawal syndrome. DESIGN: Open-label, first-in-humans trial. SETTING: A residential research facility. PARTICIPANTS: Nine physically dependent opioid-users completed the 10-day opioid detoxification study. INTERVENTION: Each volunteer received a single patch application that remained in place for 3 days. The formulation has shown an average delivery of 1.9 mg/day of buprenorphine over 3 days in pre-clinical evaluation. MEASURES: Physiological, behavioral, subjective and observer ratings of opioid withdrawal and opioid agonist effects were collected. FINDINGS: Overall, the patch appeared safe and well tolerated. There were no serious adverse events, and no opioid intoxication following patch application. Oxygen saturation, heart rate, blood pressure, skin temperature and pupil diameter remained well within normal ranges. Buprenorphine blood levels peaked 48 hours after patch application at a concentration of 0.60 ng/ml. Volunteers' self-reports of the presence and severity of withdrawal symptoms were reduced by approximately 50% on the 3 days of patch application. Withdrawal symptoms increased marginally upon patch removal. Administration of opioid rescue medication was eliminated within 6 hours of patch application, and increased slightly upon patch removal. CONCLUSIONS: The significant biodelivery of buprenorphine and the suppression of the opioid withdrawal syndrome during patch application and its reappearance after patch removal indicate clinically useful pharmacodynamic activity. Transdermal buprenorphine may be a useful opioid detoxification treatment that reduces compliance concerns, and delivers buprenorphine in a formulation less likely to be diverted to illicit use.

Self-administration of heroin produces alterations in the expression of inducible nitric oxide synthase.

Nitric oxide plays a critical role in the immune response, and our studies have shown that heroin induces a reduction in the expression of iNOS, the enzyme responsible for nitric oxide production. The present study evaluated the effect of heroin self-administration on iNOS expression using a three-group design. Group one (self-administration) was trained to press a lever for i.v. administration of heroin. Group two (yoked heroin) received a simultaneous equivalent infusion of heroin determined by the responses of a 'partner' animal in the first group. A third group (yoked saline) also was yoked to the first group, but received i.v. injections of saline. Immediately following the last session, all rats received an injection of lipopolysaccharide (LPS) to induce iNOS expression. About 6 h after the injection of LPS, iNOS mRNA and protein expression were determined in spleen, lung, and liver. Additionally, the accumulation of plasma nitrite/nitrate, the more stable end products of nitric oxide degradation were measured. Although there was not a consistent difference between the self-administering and yoked-heroin animals, the results show that rats will self-administer a sufficient amount of heroin to induce a pronounced, widespread reduction in the expression of iNOS.