Addictive Behaviors 42 (2015) 69–72

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Addictive Behaviors

Short Communication

Varenicline for opioid withdrawal in patients with chronic pain: A randomized, single-blinded, placebo controlled pilot trial☆ W. Michael Hooten ⁎, David O. Warner Department of Anesthesiology, Mayo College of Medicine, Rochester, MN, United States

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Available online 15 November 2014 Keywords: Varenicline Opioid withdrawal Chronic pain

a b s t r a c t Background and objectives: The objectives of this randomized, single-blinded, placebo-controlled pilot trial were to investigate the effects of varenicline on opioid withdrawal among chronic pain patients undergoing opioid detoxification in an interdisciplinary pain program and the feasibility of varenicline use in this population. Methods: Twenty-one patients were recruited (varenicline = 10, placebo = 11), and 7 patients in the varenicline and 11 in the placebo group completed the study. Opioid withdrawal was quantified using the Clinical Opiate Withdrawal Scale, and varenicline-related adverse effects were assessed. Results: Opioid withdrawal scores tended to decrease over the course of opioid tapering in those receiving varenicline and increase in those receiving placebo. Varenicline was well-tolerated in this population, with no adverse drug effects (including nausea) observed and no effect on improvements in pain severity and depression. Conclusions: This randomized pilot study provides preliminary data for future trials of varenicline in opioiddependent adults with chronic pain undergoing medically directed opioid detoxification. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction The use of prescription opioids for chronic pain has increased dramatically over the past two decades (Boudreau et al., 2009). Consequently, targeted clinical strategies to facilitate opioid detoxification are needed for adults with chronic pain who are motivated to discontinue long-term opioid therapy. Recent evidence suggests that nicotinic acetylcholine receptors (nAChRs) play an important role in the neurobiology of opioid dependence, and these receptors may be potential pharmacotherapeutic targets for medically-directed opioid detoxification (Hadjiconstantinou & Neff, 2011). Varenicline, an α4ß2 nAChR partial agonist and α7 nAChR full agonist, is an effective medication for smoking cessation, but the feasibility of using the drug in adults undergoing opioid detoxification and the potential effects of the drug on symptoms of opioid withdrawal are not known (Biala, Staniak, & Budzynska, 2010). The purpose of this randomized, single-blinded, placebo-controlled pilot trial was to obtain preliminary data regarding whether varenicline could ameliorate the severity of opioid withdrawal symptoms in adults with chronic pain undergoing medically directed opioid detoxification as part of an interdisciplinary pain treatment program. A secondary

☆ The research was conducted at the Mayo Pain Rehabilitation Center, Department of Psychiatry and Psychology, and the Translational Research Unit for Chronic and Acute Pain, Department of Anesthesiology, Mayo Clinic, Rochester, MN. ⁎ Corresponding author at: Department of Anesthesiology, Mayo College of Medicine, Rochester, MN 55905, United States. Tel.: +1 507 284 2511. E-mail address: [email protected] (W.M. Hooten).

http://dx.doi.org/10.1016/j.addbeh.2014.11.007 0306-4603/© 2014 Elsevier Ltd. All rights reserved.

aim was to investigate the feasibility and safety of varenicline use in this patient population; although varenicline has been administered safely to non-smokers, there is no experience with utilizing varenicline in opioid-dependent patients. 2. Methods The study was approved by the Mayo Foundation Institutional Review Board and written informed consent was obtained from all study participants. 2.1. Setting The study was conducted within Comprehensive Pain Rehabilitation Center Interdisciplinary Treatment Program (ITP) at Mayo Clinic, Rochester, MN. The ITP is of 3-week duration, and a cognitive behavioral model serves as the basis for treatment. Admissions occur on a revolving basis with patients attending 8 h daily for 15 consecutive working days. The primary goal of treatment was functional restoration. 2.2. Participants Patients were recruited at the time of admission to the ITP from June 2011 to May 2012. Inclusion criteria included 1) age ≥21 years, 2) daily morphine equivalent dose ≥60 mg, and 3) non-cancer chronic pain N 6 months duration. Exclusion criteria included 1) current use of varenicline, and 2) history of a major cardiovascular, pulmonary, surgical or psychiatric condition that would limit full participation in the ITP.

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2.3. Randomization and procedure

2.6. Data analysis

Patients were randomly assigned to the varenicline or placebo group using a computer-generated randomization schedule stratified by smoking status (current vs. former and never smokers) and administered by research pharmacy personnel not involved in trial conduct. Patients and all clinical personnel, except the principal investigator (WMH), were blinded to group allocation. Because varenicline has not been previously used in the setting of opioid detoxification, the principal investigator was not blinded so that any adverse medication effects could be immediately identified and treated. All research assessments were performed by blinded personnel. Identically-appearing varenicline and placebo tablets were prepared by the research pharmacy. The first dose of varenicline or placebo was administered on day 1 of the ITP. Varenicline was started at a dose of 0.5 mg once daily for days 1 to 3, followed by 0.5 mg twice daily for days 4 to 7, then 1 mg twice daily for days 8 to 15. For those participants who were current cigarette smokers, no specific intervention was performed to encourage smoking cessation.

Baseline demographic and clinical characteristics were summarized using the median and 25th to 75th interquartile range (IQR) for continuous variables, and frequency and proportion for categorical variables. The daily COWS scores for individual patients fluctuated considerably over time, and were not available over the weekends. Also, baseline scores prior to the initiation of varenicline were not available. Thus, to determine trends in scores during detoxification, linear regressions were performed using the COWS scores for each individual patient over the treatment period and the slopes were analyzed. Repeated measures assessment of depression and pain was performed using nonparametric tests (Wilcoxon Signed Ranks test). The level of significance for all tests was P b 0.05, and all analyses were completed using SPSS, version 21.0 (IBM, Chicago, IL).

2.4. Opioid detoxification Opioid detoxification is a well-established component of the ITP, with the opioid medication identified at admission determining each individual's taper schedule (Hooten, Mantilla, Sandroni, & Townsend, 2010). Due to the large number of available opioid medications and broad range of dosages, predetermined tapering schedules were not used, but all aimed to eliminate opioid use by the conclusion of the ITP. The daily opioid dose was converted to daily morphine equivalents using an equianalgesic conversion software program. The status of opioid use was biochemically confirmed by urine toxicology screening at admission and completion of the opioid taper. All opioid tapers were medically directed (WMH).

2.5. Assessments 2.5.1. Demographics and clinical characteristics Baseline demographic and clinical characteristics were collected at admission.

2.5.2. Tolerability of varenicline and severity of opioid withdrawal Patients were assessed daily for signs and symptoms of vareniclinerelated adverse side effects (nausea and vomiting, worsening depression, suicidality, worsening pain) severe enough to warrant discontinuation of the medication. Because the signs and symptoms of opioid withdrawal may be difficult to differentiate from varenicline-related adverse side effects, medication discontinuation was used to assess the feasibility of varenicline use in this patient population. The severity of opioid withdrawal symptoms was assessed using the Clinical Opiate Withdrawal Scale (COWS) (Wesson & Ling, 2003). Symptoms of opioid withdrawal were assessed during each working day (between 9:00 and 10:00 AM) during the course of detoxification as a part of normal clinical practice by clinical personnel.

2.5.3. Pain severity and depressive symptoms Pain was assessed at baseline and program dismissal using the pain severity subscale of the Multidimensional Pain Inventory (Kerns, Turk, & Rudy, 1985). Raw scores were converted to standardized t-scores with a normative value of 50 (range 0–100, standard deviation 10). Depressive symptoms were assessed at the same time points using the Center for Epidemiologic Studies––Depression scale (CES-D), which has established reliability and validity in adults with chronic pain (Radloff, 1977).

3. Results Twenty-one patients were randomized (varenicline = 10, placebo = 11). Three patients allocated to the varenicline group withdrew from the study. One patient withdrew from both the study and the ITP prior to taking study medication 4 days following admission due to discrepant treatment expectations. Two patients, both with histories of polysubstance abuse, withdrew from the study on days 5 and 7, stating that study participation was a distraction from ITP participation. Both patients completed the ITP, and were referred for further treatment of polysubstance abuse. No adverse drug effects were reported or observed in these two patients. Successful opioid detoxification was biochemically verified upon completion of the ITP for each study participant. For those patients who completed the study procedures (varenicline = 7, placebo = 11), the majority were Caucasian males, and no statistically significant group differences were observed between groups (all P values N 0.1) (Table 1). Morphine equivalent doses at the beginning of treatment were similar among groups. Similar proportions of participants were current cigarette smokers, and all of these participants continued to smoke over the course of the ITP.

3.1. Opioid withdrawal symptoms and varenicline tolerability The median time to completion of opioid tapering was 18 days (IQR, 14 to 19) for the varenicline group and 15 days (IQR, 14 to 17) for the placebo group (P N 0.1). Fig. 1 depicts the regression lines of the daily COWS scores for each patient. The median value of the regression coefficients of the varenicline group was − .116 (IQR, − .248 to .025), and the median of the placebo group was .086 (IQR, − .264 to .332) (P = .258). The slope of the regression was negative (indicating decreases over time) in 5 of the 7 (71%) patients receiving varenicline and 4 of the 11 patients receiving placebo (36%) (P = .334, Fischer's exact test). This indicates that opioid withdrawal symptoms tended to decrease over time in those treated with varenicline and tended to increase over time in the placebo group. No adverse effects were observed among patients in either group; in particular, no patient complained of nausea.

3.2. Pain and depression Table 1 contains the median pain severity and depression scores for the varenicline and placebo groups. Significant changes were observed for pain severity (P = .001) and depression (P b .001) scores from program admission to dismissal, indicating that patients experienced symptomatic improvements during the ITP. The changes experienced by both treatment groups were similar.

W.M. Hooten, D.O. Warner / Addictive Behaviors 42 (2015) 69–72 Table 1 Demographics and clinical characteristics. Characteristic

Age, median (IQR)a Male, N (%) Body mass index (kg/m2) Caucasian Education (years) Pain duration (years) Pain site Fibromyalgia Low back pain Neck Headache Generalized Abdominal Pelvic Upper extremity Chest wall Morphine equivalent dose (mg/day) Smoking status Current smoker Former smoker Never smoker MPI pain severitya Baseline Dismissal Change CES-Da Baseline Dismissal Change Duration of opioid taper (days)

Group Varenicline (N = 7)

Placebo (N = 11)

49.0 (36.0 to 60.0) 6 (86) 24.7 (24.4 to 31.7) 7 (100) 14.0 (13.0 to 16.0) 7.0 (5.0 to 10.0)

46.0 (29.0 to 53.0) 7 (64) 33.1 (27.4 to 39.6) 11 (100) 16.0 (12.0 to 17.0) 5.0 (2.0 to 10.0)

– 2 1 – 2 1 – 1 – 135.0 (90.0 to 180.0)

3 2 – 1 1 1 2 – 1 75.0 (60.0 to 142.5)

4 (57) – 3 (43)

5 (45) 4 (36) 2 (18)

50.6 (45.3 to 55.9) 34.6 (24.0 to 53.3) 16.0 (2.7 to 21.3)

53.3 (47.9 to 61.2) 41.3 (34.0 to 43.9) 12.0 (6.6 to 23.3)

31.0 (24.0 to 37.0) 10.0 (6.0 to 14.0) 21.0 (10.0 to 32.0) 18.0 (14.0 to 19.0)

30.0 (17.0 to 35.0) 12.0 (9.0 to 16.0) 18.0 (0.0 to 28.0) 15.0 (14.0 to 17.0)

a IQR, 25th to 75th interquartile range; pain severity subscale of the Multidimensional Pain Inventory and Centers for Epidemiologic Studies—Depression scale.

4. Discussion The main finding of this study was that opioid withdrawal scores tended to decrease over the course of opioid tapering in those receiving varenicline and increase in those receiving placebo. Varenicline was well-tolerated in this population, with no adverse drug effects (including nausea) observed and no effect on improvements in pain severity and depression.

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There is evidence from preclinical studies that nicotinic agonists could be used to treat opioid withdrawal. In rodent studies of an acute opioid withdrawal model, naloxone-induced conditioned place aversion (CPA) was attenuated by nicotine. This effect was subsequently blocked by selective α7 nAChR antagonism but not by selective α4ß2 nAChR antagonism (Motoshima et al., 2005; Cui, Suemaru, Li, Kohnomi, & Araki, 2009). Furthermore, naloxoneinduced CPA was attenuated by a selective α7 nAChR agonist microinjected into the central amygdaloid nucleus (Ishida et al., 2011). These preclinical studies suggest that the α7 nAChR agonist activity of varenicline, rather than the α4ß2 nAChR partial agonist activity of the drug, could prove useful in mitigating the signs and symptoms of opioid withdrawal in humans. Varenicline has been previously administered to nonsmokers. In a crossover design study, nonsmokers (n = 22) were administered 1 mg and 3 mg dosages of varenicline (McColl et al., 2008). Although nonsmokers experienced adverse side effects (i.e., nausea, vomiting, headache, dizziness), the majority were classified as mild to moderate, and only one nonsmoker in the 3 mg dose arm discontinued varenicline due to adverse drug effects. Our preliminary findings extend these observations and suggest that varenicline may also be feasible for use in adult nonsmokers with chronic pain undergoing opioid detoxification. This pilot study has several limitations. First, opioid tapering was initiated while patients were simultaneously titrating up the dose of varenicline. In future studies, varenicline could be titrated to recommended doses for one week prior to initiating opioid tapering, similar to the regimen recommended when varenicline is utilized for smoking cessation. Second, the potential effects of varenicline on latent clinical symptoms of opioid withdrawal, including opioid craving, were not assessed. Third, the single-blinded study design used to ensure patient safety was a potential source of bias, although the personnel making the clinical assessments were blinded. Finally, although the 2 patients who withdrew from study participation in the varenicline group did not complain of side effects, it is possible that an unarticulated effect produced by varenicline may have prompted their withdrawal. In conclusion, this randomized pilot study provides preliminary evidence that varenicline is both feasible to use in the context of opioid tapering and may be efficacious in mitigating withdrawal symptoms. Adequately powered randomized trials are indicated to further explore this indication.

Fig. 1. Regression lines fitted to the daily Clinical Opiate Withdrawal Scale (COWS) score of each individual patient in the placebo and varenicline groups.

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Role of funding sources This research was funded by the Mayo Foundation, Rochester, MN. The funding source had no role in the study design, collection, analysis, interpretation of the study data, writing of the manuscript or decision to submit the manuscript to Addictive Behaviors. Contributors All authors have participated in the design and conduct of this research. All authors contributed in data interpretation and writing of the manuscript. Conflict of interest The authors have no actual or potential conflicts of interest to report.

References Biala, G., Staniak, N., & Budzynska, B. (2010). Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 381, 361–370. Boudreau, D., Von Korff, M., Rutter, C.M., Saunders, K., Ray, G.T., Sullivan, M.D., et al. (2009). Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiology and Drug Safety, 18, 1166–1175. Cui, R., Suemaru, K., Li, B., Kohnomi, S., & Araki, H. (2009). Tropisetron attenuates naloxone-induced place aversion in single-dose morphine-treated rats: Role of alpha7 nicotinic receptors. European Journal of Pharmacology, 609, 74–77.

Hadjiconstantinou, M., & Neff, N.H. (2011). Nicotine and endogenous opioids: Neurochemical and pharmacological evidence. Neuropharmacology, 60, 1209–1220. Hooten, W.M., Mantilla, C.B., Sandroni, P., & Townsend, C.O. (2010). Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering. Pain Medicine, 11, 1587–1598. Ishida, S., Kawasaki, Y., Araki, H., Asanuma, M., Matsunaga, H., Sendo, T., et al. (2011). Alpha7 nicotinic acetylcholine receptors in the central amygdaloid nucleus alter naloxoneinduced withdrawal following a single exposure to morphine. Psychopharmacology (Berl), 214, 923–931. Kerns, R.D., Turk, D.C., & Rudy, T.E. (1985). The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain, 23, 345–356. McColl, S.L., Burstein, A.H., Reeves, K.R., Billing, C.B., Jr., Stolar, M., & Sellers, E.M. (2008). Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers. Clinical Pharmacology and Therapeutics, 83, 607–614. Motoshima, S., Suemaru, K., Kawasaki, Y., Jin, C., Kawasaki, H., Gomita, Y., et al. (2005). Effects of alpha4beta2 and alpha7 nicotinic acetylcholine receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats. European Journal of Pharmacology, 519, 91–95. Radloff, L. (1977). The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385–401. Wesson, D.R., & Ling, W. (2003). The Clinical Opiate Withdrawal Scale (COWS). Journal of Psychoactive Drugs, 35, 253–259.

Varenicline for opioid withdrawal in patients with chronic pain: a randomized, single-blinded, placebo controlled pilot trial.

The objectives of this randomized, single-blinded, placebo-controlled pilot trial were to investigate the effects of varenicline on opioid withdrawal ...
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