Journal of Substance Abuse Treatment 48 (2015) 128–131

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Journal of Substance Abuse Treatment

Buprenorphine/Naloxone Dose and Pain Intensity Among Individuals Initiating Treatment for Opioid Use Disorder William C. Becker, M.D. a,b,⁎, Dara Ganoczy, M.P.H. c, David A. Fiellin, M.D. b, Amy S.B. Bohnert, Ph.D. c,d a

VA Connecticut Healthcare System, 950 Campbell Avenue, Mail Stop 151B, West Haven, CT 06516, USA Yale University School of Medicine, E.S. Harkness Building A, 367 Cedar Street, Suite 406A, New Haven, CT 06510, USA Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Department of Veterans Affairs, 2215 Fuller Road (11H), Ann Arbor, MI 48105, USA d Department of Psychiatry, University of Michigan, 4250 Plymouth Road, Ann Arbor, MI 48109, USA b c

a r t i c l e

i n f o

Article history: Received 9 June 2014 Received in revised form 14 September 2014 Accepted 16 September 2014 Keywords: Opioid use disorder Pain Treatment Buprenorphine/Naloxone

a b s t r a c t Background: Opioid use disorder and pain often co-occur, complicating the treatment of each condition. Owing to its partial agonist properties, buprenorphine/naloxone (BUP/NX) may confer advantages over full agonist opioids for treatment of both conditions. The optimal dose of BUP/NX for comorbid pain is not known. We examined dose and other factors associated with pain intensity among patients initiating BUP/NX for opioid use disorder. Methods: We studied 1106 patients initiating BUP/NX treatment for opioid use disorder from 2003 to 2010. Information on pain level, diagnoses, and treatment were extracted from medical records. Eligible patients had at least one self-reported pain intensity numerical rating score (NRS) within 30 days before BUP/NX initiation (baseline) and at least one between 15 and 90 days after BUP/NX initiation (during treatment). The primary outcome was NRS decrease (2 or greater) from baseline to during treatment. We used generalized estimating equations to model odds of the primary outcome with BUP/NX dose as the independent variable of interest in the subset of patients with a baseline NRS ≥ 2. Results: The sample was 94% male and 73% White. Mean age was 50. Psychiatric and non-opioid substance use comorbidities were common. The following demographic and clinical correlates were associated with a decrease in pain intensity: age 18–29 (compared to 30–39 and 40–49); absence of PTSD diagnosis and absence of a chronic pain diagnosis. BUP/NX dose was not associated with decreased pain intensity in bivariate or multivariable analysis. Conclusions: BUP/NX maintenance treatment was generally consistent with improvements in pain intensity; however, factors other than BUP/NX dose contribute to improved pain intensity among those initiating the medication. Published by Elsevier Inc.

1. Introduction Chronic pain is present in 38% to 55% of patients initiating opioid agonist treatment of opioid use disorder and can impact treatment outcomes (Barry et al., 2012, 2013; Brands, Blake, Sproule, Gourlay, & Busto, 2004; Potter, Shiffman, & Weiss, 2008; Potter et al., 2010). The complex interaction between pain and opioid use disorder has spurred interest in how chronic pain may affect opioid agonist treatment response, and, in turn, how opioid agonist treatment may be tailored to improve effectiveness among patients with comorbid chronic pain. The focus of the present study is buprenorphine/naloxone (BUP/NX), which, owing to its predominantly partial opioid agonist mechanism of action when taken sublingually, (Chiang & Hawks, 2003) may confer less risk of opioid-related adverse effects and opioid-induced hyperalgesia and less reward-reinforcement compared to full agonist opioids (Pergolizzi et al., 2010). As such, BUP/NX holds promise in its ⁎ Corresponding author at: VA Connecticut Healthcare System, Mail Stop 151B, 950 Campbell Avenue, West Haven, CT 06516. Tel.: + 1 203 932 5711x2427; fax: + 1 203 479 8126. E-mail address: [email protected] (W.C. Becker). http://dx.doi.org/10.1016/j.jsat.2014.09.007 0740-5472/Published by Elsevier Inc.

dual effect role for treatment of patients with opioid use disorder and chronic pain. Furthermore, there may be BUP/NX treatment strategies, e.g., modifying dose, that may be more effective in patients with cooccurring chronic pain and opioid use disorder (Chakrabarti, Woody, Griffin, Subramaniam, & Weiss, 2010) although there is limited empirical research on these issues (Heit & Gourlay, 2008). The purpose of the present study was to explore the relationship between dose of BUP/NX and pain intensity among patients initiated on BUP/NX for the treatment of opioid use disorder. Additionally, we sought to assess the demographic and clinical correlates of a clinically-meaningful improvement in pain intensity after BUP/NX initiation. 2. Methods The study protocol was approved by the Ann Arbor VA Human Investigations Committee. Data were from fiscal years 2003–2010; sources included the Veterans Health Administration's National Patient Care Database (demographic and clinical data), Corporate Data Warehouse (pain scores) and Pharmacy Benefits Management Services. Included patients met the following criteria: (1) initiation of BUP/NX, defined as a fill of BUP/NX in the pharmacy record and no fills of BUP/

W.C. Becker et al. / Journal of Substance Abuse Treatment 48 (2015) 128–131

NX in the prior 90 days; (2) opioid abuse or dependence diagnosis, per ICD-9-CM coding in the month of the first BUP/NX fill or the year prior; (3) at least one patient-reported pain numerical rating scale (NRS) score in the 30 days prior to BUP/NX initiation, defined as “baseline,” excluding scores that were during a non-psychiatric inpatient stay; (4) at least one NRS during the BUP/NX treatment period between 15 and 90 days after BUP/NX initiation, excluding scores that were during a non-psychiatric inpatient stay; and (5) dose, total quantity and days supplied on the treatment episode BUP/NX prescription, allowing for calculation of daily dose (buprenorphine component). An individual patient could have had multiple observation periods (i.e., for multiple new starts of BUP/NX) if a 90-day period elapsed between the end of one fill of BUP/NX and the beginning of the next BUP/NX fill. For patients who discontinued BUP/NX treatment (i.e., the days supplied from one BUP/ NX fill passed and another BUP/NX fill did not occur for 15 days), observation ended for that episode of treatment on the date the last BUP/NX fill was scheduled to run out. The primary outcome of the study was change in patient-reported pain intensity, measured by NRS, from baseline to during BUP/NX treatment. For patients who had more than one NRS during the treatment episode, we used the monthly mean NRS to serve as the comparison to baseline. The independent variable of interest was average monthly BUP/NX dose at the time of the during-treatment NRS. We calculated daily BUP/NX dose by multiplying the dose by the total quantity divided by the days supplied; daily dose was categorized as b 9 mg, 9 mg to b17 mg, 17 mg to b 25 mg and 25 mg or greater. Covariates included demographic (age, sex, race/ethnicity) and clinical data (pain, medical, psychiatric and addiction diagnoses based on ICD-9 codes). Pain diagnoses were categorized as chronic pain, including several diagnoses that are likely associated with pain such as 722 (intervertebral disc disorders); headache; acute pain, including several diagnoses such as chest pain and fracture; neuropathy; fibromyalgia; and chronic pain syndrome, which is a single ICD code. The ICD codes used for each category were mutually exclusive, but a patient could belong to more than one category. Additionally, pre-BUP/NX treatment morphine equivalent daily opioid dose was included as a covariate for those patients prescribed opioid analgesics within 30 days of BUP/NX initiation. We used descriptive statistics to summarize baseline demographic and clinical characteristics and the distribution of BUP/NX dose levels (see Table 1) and bivariate measures to assess the relationship between independent variables and change in pain intensity. To test the adjusted associations between BUP/NX dose and change in pain intensity, we used a mixed effects model with BUP/NX dose as a between-subject factor and time since initiating treatment (in months) as a within-subject factor. Mixed-effects modeling accommodated different numbers of observations per subject and randomly missing data and allowed for use of all available data. To assess demographic and clinical correlates of a clinically-meaningful change in pain intensity, we first defined an improvement of two points or greater on the NRS as such a change based on review of the literature (Farrar, Young, LaMoreaux, Werth, & Poole, 2001). We then excluded all patients with a baseline NRS of b 2 because clinically-meaningful improvement under this definition would not have been possible. Finally, we used generalized estimating equations to model odds of an NRS improvement of 2 points or greater, with BUP/NX dose as the independent variable of interest and other covariates listed above in the model. 3. Results The sample included 1106 patients with a mean age of 50 of whom 94% were men, 73% were White, 24% were Black and 10% were Hispanic. Pain diagnoses were widely prevalent, with 71% of the sample having a chronic pain diagnosis. Psychiatric comorbidity was also common in the sample: 30% had post-traumatic stress disorder (PTSD), 63% had major depression and 41% had other serious mental illnesses. Substance use disorders (in addition to opioid use disorder) were also widely

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Table 1 Description of full sample (N = 1106).a Proportion of sample, n (%) Age 18–29 30–39 40–49 50–59 60–69 70 and older Sex: Female Male Race: White Black Other/Unknown Ethnicity: Hispanic Non-Hispanic/Unknown Post-traumatic stress disorder No Major depression No Other serious mental illness No Alcohol use disorder No Substance use disorder No COPD, sleep apnea or cardiovascular disease No Cancer No Diabetes No Chronic pain No Headache No Acute pain No Neuropathy No Fibromyalgia No Chronic pain syndrome No Buprenorphine/Naloxone dose, maximum b9 9 mg to b17 mg 17 mg to b25 mg 25 mg or greater a b

Mean change in pain intensityb

P value

110 (9.4) 126 (10.8) 227 (19.4) 565 (48.3) 135 (11.5) 8 (0.7)

−0.44 −0.11 −0.16 −0.46 −0.37 0.30

.7648

70 (6.0) 1101 (94.0)

0.21 −0.38

.1139

851 (72.7) 275 (23.5) 45 (3.8)

−0.43 −0.04 −0.58

.2921

115 (9.8) 1056 (90.2) 348 (29.7) 823 (70.3) 735 (62.8) 436 (37.2) 476 (40.7) 695 (59.4) 516 (44.1) 655 (55.9) 875 (74.7) 296 (25.3) 700 (59.8)

−0.49 −0.33 −0.15 −0.43 −0.18 −0.62 −0.28 −0.39 −0.46 −0.26 −0.25 −0.63 −0.37

.9449

471 (40.2) 125 (10.7) 1046 (89.3) 171 (14.6) 1000 (85.4) 835 (71.3) 336 (28.7) 130 (11.1) 1041 (88.9) 337 (28.8) 834 (71.2) 54 (4.6) 1117 (95.4) 48 (4.1) 1123 (95.9) 66 (5.6) 1105 (94.4)

−0.31 −0.94 −0.27 −0.37 −0.34 −0.39 −0.23 −0.54 −0.32 −0.43 −0.31 −0.64 −0.33 0.002 −0.36 −0.72 −0.32

288 (24.6) 433 (37.0) 271 (23.1) 179 (15.3)

−0.37 −0.36 −0.31 −0.44

.1039 .0303 .5446 .2624 .2266 .5943

.0272 .7405 .2520 .3666 .5111 .2610 .5647 .2356

.8163

Includes 1171 treatment episodes. Negative change indicates decrease in pain score.

prevalent: 44% of the sample had alcohol use disorder and 75% had a non-opioid substance use disorder. The majority of patients in the study had only one BUP/NX treatment episode (95%) while 5% had two and 0.4% had 3. There was a wide distribution of BUP/NX dosing, with 25% of the sample prescribed a maximum dose of b 9 mg, 37% prescribed from 9 mg to b17 mg, 23% from 17 mg to b 25 mg and 15% 25 mg or greater. Comparing pre-BUP/NX to within BUP/NX treatment, mean change in pain intensity was improved (i.e., negative) for all demographic and clinical categorizations except individuals 70 years and older and women. In bivariate analyses, individuals without major depression had a significantly greater improvement in pain compared to those with major depression, and those with cancer had a significantly greater improvement in pain compared to those without cancer. There was no significant difference between BUP/NX dose categories and change in pain score. In the reduced sample of patients with a baseline

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Table 2 Odds of clinically significant improvement in paina (N = 776).

Age 18–29 30–39 40–49 50–59 60–69 70 and older Sex: Female Male Race: White Black Other/Unknown Ethnicity: Hispanic Non-Hispanic/ Unknown PTSD No Major depression No Other serious mental illness No Alcohol use disorder No Substance use disorder No COPD, sleep apnea or cardiovascular disease No Cancer No Diabetes No Chronic pain No Headache No Acute pain No Neuropathy No Fibromyalgia No Chronic pain syndrome No Buprenorphine/ Naloxone dose b9 9 mg to b17 mg 17 mg to b25 mg 25 mg or greater a

Proportion of sample N 2, n (%)

P value

Adjusted odds ratio (95% CI)

64 (8.3) 81 (10.4) 150 (19.3) 380 (49.0) 96 (12.4) 5 (0.6)

ref .0266 .0341 .0748 .0724 .3854

ref 0.50 (0.27,0.92) 0.51 (0.28,0.95) 0.59 (0.33,1.05) 0.54 (0.27, 1.06) 0.36 (0.03, 3.65)

49 (6.3) 727 (93.7)

ref ref .1357 1.59 (0.86, 2.93)

580 (74.7) 163 (21.0) 33 (4.3)

ref ref .4271 0.86 (0.60, 1.25) .7899 1.11 (0.52, 2.34)

67 (8.6) 709 (91.4)

.5641 1.14 (0.73, 1.79) – –

245 (31.6) 531 (68.4) 508 (65.5) 268 (34.5) 340 (43.8)

.0108 – .2472 – .2828

0.68 (0.51, 0.92) – 0.83 (0.61, 1.13) – 0.86 (0.65, 1.14)

436 (56.2) 343 (44.2) 433 (55.8) 588 (75.8)

– .1367 – .1794

– 1.23 (0.94, 1.60) – 1.27 (0.90, 1.80)

188 (24.2) 480 (61.9)

– – .1972 1.23 (0.90, 1.68)

296 (38.1) 94 (12.1) 682 (87.9) 116 (15.0) 660 (85.1) 621 (80.0) 155 (20.0) 101 (13.0) 675 (87.0) 256 (33.0) 520 (67.0) 42 (5.4) 734 (94.6) 40 (5.2) 736 (94.9) 58 (7.5) 718 (92.5)

– .1190 – .6240 – .0439 – .4254 – .2730 – .3026 – .6051 – .8190 –

– 1.37 (0.92, 2.02) – 1.11 (0.74, 1.65) – 0.69 (0.48, 0.99) – 1.18 (0.79, 1.75) – 0.84 (0.62, 1.15) – 0.70 (0.36, 1.37) – 0.84 (0.43, 1.63) – 0.94 (0.56, 1.58) –

177 (22.8) 284 (36.6) 190 (24.5) 125 (16.1)

ref .3444 .0594 .4751

ref 0.86 (0.62, 1.18) 0.67 (0.44, 1.02) 0.82 (0.47, 1.42)

Among patients with baseline pain score ≥ 2.

NRS of ≥2, multivariable modeling revealed that age 18–29 (compared to 30–39 and 40–49); absence of PTSD and absence of chronic pain were associated with increased odds of a clinically-meaningful improvement in pain (Table 2). BUP/NX dose was not independently associated with a clinically-meaningful improvement in pain score in this model. 4. Discussion In this retrospective cohort study of 1106 individuals initiating BUP/ NX for opioid use disorder, of whom 81% had a pain-related diagnosis, we found no association between BUP/NX dose and pain score nor clinically-meaningful improvement in pain after adjustment for

demographic and clinical factors, including pain diagnosis. However, regardless of dose, on average the vast majority of patients experienced improvement in pain, albeit modestly so for most. Our findings that certain subgroups of patients had improved analgesic response with BUP/ NX may have implications for clinical care and future studies, as discussed below. There are a variety of potential explanations for our finding of a lack of association between BUP/NX dose and change in pain score. First, the effective analgesic dose of BUP/NX may occur at much lower than the doses with demonstrated efficacy in treating opioid use disorder (Bullingham, McQuay, Dwyer, Allen, & Moore, 1981). Relatedly, there may be a plateau of BUP/NX's analgesic effect that occurs at a relatively low dose. If the analgesic plateau dose is, for example, 4 mg daily as some have speculated (Johnson, Fudala, & Payne, 2005), those above that dose—the vast majority of study participants—may have experienced a relatively uniform analgesic effect, regardless of how high above 4 mg their dose was. Another potential explanation for the observed absence of association between dose and pain improvement is that, clinically, providers may have intentionally or unintentionally titrated BUP/NX to analgesic effect. In other words, individual patients may have been stabilized on doses that had maximum efficacy for their pain. In a non-randomized observational study such as this one, this selection effect may obscure the relationship between dose and pain level due to non-random treatment decisions. Additionally, the lack of association between BUP/NX dose and pain level may be due to a limited analgesic effect of BUP/NX across the entire dose range. The mean change in pain intensity was modest across the entire sample, ranging from a nearly 1 point improvement among patients with cancer to no improvement among patients with fibromyalgia. Modest changes in pain intensity may also be related to a floor effect: many patients in our sample had low levels of pain to begin with, meaning a diminished opportunity for BUP/NX to have a marked effect on change in average pain score. Finally, differences may exist that we were not powered sufficiently to detect. Our finding that certain subgroups of patients had a more robust analgesic response to BUP/NX deserves further consideration. Patients without major depression had a greater improvement in pain compared to those with depression. This may reflect a common clinical and experimental finding—co-occurring depression often makes pain more difficult to treat (Kroenke et al., 2009). That patients with cancer were more likely to have improved pain intensity with initiation of BUP/NX may be explained by the fact that patients with cancer were more likely to have pain, and pain of greater severity, than those without and thus more of an opportunity to experience analgesic benefit from BUP/NX. The youngest age group in our study and individuals without chronic pain were more likely to experience a clinically-meaningful improvement in pain; these findings suggest that the longer pain persists, the more refractory to opioid treatment it may become, a potential consequence of neuronal plasticity and central sensitization (Woolf & Salter, 2000). Individuals with PTSD were less likely to experience a clinically significant improvement in pain, which, as with major depression, may be a function of the known relationship between PTSD and worsened pain (Clapp, Beck, Palyo, & Grant, 2008). Our study has limitations. First, the predominance of men in the sample means results may not generalize to women. Second, the measurement of pain using NRS has inherent limitations such as interindividual variation in the experience associated with any given pain score; however, changes in pain scores have been shown to generalize within and across samples (Farrar et al., 2001; Goulet et al., 2013). Additionally, by measuring only pain intensity, we may have missed other potential beneficial pain-related effects of BUP/NX such as improvement in function. Finally, the reliance on administrative data and diagnostic codes to characterize the sample likely led to a loss of validity; however, there was unlikely to be a differential loss of validity that would have biased our results.

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5. Conclusions Our study suggests that while most individuals have improved pain with the initiation of BUP/NX, factors other than dose may influence the response, or, perhaps, individualized doses may be the most appropriate approach. Randomized trials are needed to fully account for known and unknown confounders. Acknowledgments This work was supported by the VA's Office of Research and Development, Health Services Research [CDA2 (08-276)] and the Substance Use Disorder QUERI (SUDQ-LIP1302). Study sponsors had no role in study design; in the collection, analysis and interpretation of data; neither in the writing of the manuscript nor in the decision to submit the manuscript for publication. Dr. Fiellin has received honorarium for serving on an external advisory board monitoring the diversion and abuse of buprenorphine from Pinney Associates. References Barry, D. T., Savant, J. D., Beitel, M., Cutter, C. J., Moore, B. A., Schottenfeld, R. S., et al. (2012). Use of conventional, complementary, and alternative treatments for pain among individuals seeking primary care treatment with buprenorphine-naloxone. Journal of Addiction Medicine, 6, 274–279 (210.1097/ADM.1090b1013e31826d31821df31823). Barry, D. T., Savant, J. D., Beitel, M., Cutter, C. J., Moore, B. A., Schottenfeld, R. S., et al. (2013). Pain and associated substance use among opioid dependent individuals seeking office‐based treatment with buprenorphine–naloxone: A needs assessment study. The American Journal on Addictions, 22, 212–217. Brands, B., Blake, J., Sproule, B., Gourlay, D., & Busto, U. (2004). Prescription opioid abuse in patients presenting for methadone maintenance treatment. Drug and Alcohol Dependence, 73, 199–207.

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