- Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis. [JOURNAL ARTICLE]
- PLoS One 2016; 11(7):e0158851.
Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.
- Should the United States Government Repeal Restrictions on Buprenorphine/Naloxone Treatment? [JOURNAL ARTICLE]
- Subst Use Misuse 2016 Jul 27.:1-6.
Attention must be focused on needed changes to the current United States law that restricts physicians who prescribe buprenorphine for the detoxification or treatment of Opioid Use Disorder, to accepting no more than 100 patients. The current system does not provide comprehensive treatment as defined by the American Society of Addiction Medicine (ASAM) criteria. In addition, it suffers from both fragmentation and stigma and will require a significant change to comply with ASAM's call for integrated delivery of comprehensive addiction treatment. This commentary calls for the development and implementation of "best practice," by recommending caution in lifting the 100 patient limit until substantial achievement of this goal occurs. The authors call for an increase to 200 in the patient limit to be restricted to those physicians who are Board Certified in Addiction Medicine by the American Board of Addiction Medicine (ABAM) or in Addiction Psychiatry by the American Board of Psychiatry and Neurology (ABPN), or other responsible medical organizations. Any additional restriction lifting should follow a systemic evolution that rewards and documents competency. Such a system would involve the integration of treatment, treatment systems, and recovery with prescription medication. In addition, it should monitor emotional blunting, treatment progress and initiation of genetic addiction risk testing.
- Predictors of early dropout in outpatient buprenorphine/naloxone treatment. [JOURNAL ARTICLE]
- Am J Addict 2016 Jul 21.
Identifying predictors of early drop out from outpatient treatment of opioid use disorder (OUD) with buprenorphine/naloxone (BN) may improve care for subgroups requiring more intensive engagement to achieve stabilization. However, previous research on predictors of dropout among this population has yielded mixed results. The aim of the present study was to elucidate these mixed findings by simultaneously evaluating a range of putative risk factors that may predict dropout in BN maintenance treatment.Outpatient medical records and weekly supervised urine toxicology results were retrospectively reviewed for patients at two community psychiatric clinics (n = 202): a private hospital clinic (n = 84) and a federally qualified health center (n = 118). A forward stepwise logistic regression was utilized to investigate the association between early dropout (i.e., discontinuing treatment or buprenorphine non-adherence within the first 3 months of clinic entry) and extracted sociodemographic, clinical, substance use, and treatment history variables.Overall, 56 of 202 participants (27.7%) dropped out of treatment. The multivariable analysis indicated that age under 25 (B = 1.47, SEB = .52, p < .01) and opioid use in month 1 (B = 1.50, SEB = .41, p < .001) were significantly associated with early dropout; those with a history of suicide attempt were significantly less likely to drop out (B = -1.44, SEB = .67, p < .05).Consistent with previous research, younger age and use of opioids during the first month of treatment predicted early dropout. Having a history of prior suicide attempt was associated with 3-month BN treatment retention, which has not been previously reported. (Am J Addict 2016;XX:1-6).
- Factors associated with physical and sexual violence by police among people who inject drugs in Ukraine: implications for retention on opioid agonist therapy. [Journal Article]
- J Int AIDS Soc 2016; 19(4 Suppl 3):20897.
Ukraine's volatile HIV epidemic, one of the largest in Eastern Europe and Central Asia, remains concentrated in people who inject drugs (PWID). HIV prevalence is high (21.3% to 41.8%) among the estimated 310,000 PWID. Opioid agonist therapy (OAT) is the most cost-effective HIV prevention strategy there, yet OAT services are hampered by negative attitudes and frequent harassment of OAT clients and site personnel by law enforcement. This paper examines the various types of police violence that Ukrainian PWID experience and factors associated with the different types of violence, as well as the possible implications of police harassment on OAT retention.In 2014 to 2015, we conducted a cross-sectional survey in five Ukrainian cities with 1613 PWID currently, previously and never on OAT, using a combination of respondent-driven sampling, as well as random sampling. We analysed correlates of police violence by multiple factors, including by gender, and their effects on duration of OAT retention. Self-reported physical and sexual violence by police were the two primary outcomes, while retention on OAT was used as a secondary outcome.Overall, 1033 (64.0%) PWID reported being physically assaulted by police, which was positively correlated with currently or previously being on OAT (69.1% vs. 60.2%; p<0.01). HIV prevalence rates were higher in those receiving OAT than those not on OAT (47.6% vs. 36.1%; p<0.01). Police violence experiences differed by sex, with men experiencing significantly more physical violence, while women experienced more sexual violence (65.9% vs. 42.6%; p<0.01). For PWID who had successfully accessed OAT, longer OAT retention was significantly correlated both with sexual assault by police and fewer non-fatal overdoses.Police violence is a frequent experience among PWID in Ukraine, particularly for those accessing OAT, an evidence-based primary and secondary HIV prevention strategy. Police violence experiences, however, were different for men and women, and interventions with police that address these sexual differences and focus on non-violent interactions with PWID to improve access and retention on OAT are crucial for improving HIV prevention and treatment goals for Ukraine.
- Acceptability of the use of cellular telephone and computer pictures/video for "pill counts" in buprenorphine maintenance treatment. [Journal Article]
- J Opioid Manag 2016 May-Jun; 12(3):217-20.
As part of a comprehensive plan to attempt to minimize the diversion of prescribed controlled substances, many professional organization and licensing boards are recommending the use of "pill counts." This study sought to evaluate acceptability of the use of cellular phone and computer pictures/video for "pill counts" by patients in buprenorphine maintenance treatment.Patients prescribed buprenorphine/naloxone were asked a series of questions related to the type(s) of electronic communication to which they had access as well as their willingness to use these for the purpose of performing a "pill/film count."Of the 80 patients, 4 (5 percent) did not have a phone at all. Only 28 (35 percent) had a "smart phone" with some sort of data plan and Internet access. Forty (50 percent) of the patients had a phone with no camera and 10 (12.5 percent) had a phone with a camera but no video capability. All patients said that they would be willing to periodically use the video or camera on their phone or computer to have buprenorphine/naloxone pills or film counted as long as the communication was protected from electronic tampering.With the advent of applications for smart phones that allow for Health Insurance Portability and Accountability Act of 1996-compliant picture/video communication, a number of things can now be done that can enhance patient care as well as reduce the chances of misuse/diversion of prescribed medications. This could be used in settings where a larger proportion of controlled substances are prescribed including medication assisted therapy for opioid use disorders and pain management programs.
- Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2016 Jul 19; 316(3):282-90.
The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion.To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence.Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician.Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks).The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting.Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively.Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings.clinicaltrials.gov Identifier: NCT02180659.
- Efficacy and Tolerability of Buccal Buprenorphine in Opioid-Experienced Patients With Moderate to Severe Chronic Low Back Pain: Results of a Phase 3, Enriched Enrollment, Randomized Withdrawal Study. [JOURNAL ARTICLE]
- Pain 2016 Jul 18.
A buccal film of buprenorphine (BBUP) was evaluated for safety and efficacy in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized withdrawal study in opioid-experienced patients (30 to ≤160 mg/d morphine sulfate equivalent [MSE]) with moderate to severe chronic low back pain (CLBP) taking around-the-clock opioid analgesics. Patients' opioid doses were tapered to ≤30 mg MSE before open-label titration with BBUP (range, 150-900 μg every 12 hours). Patients who responded (received adequate analgesia that was generally well tolerated for 14 days) were randomized to receive buprenorphine (n=254) or placebo (n=257) buccal film. The primary efficacy variable was change from baseline to week 12 of double-blind treatment in mean average daily pain-intensity scores using a rating scale of 0 (no pain) to 10 (worst pain imaginable). In the intent-to-treat population, mean pain scores were 6.7 following opioid taper and declined to 2.8 after the BBUP titration period. After randomization, mean pain scores were lower in the BBUP group than in the placebo group; the difference between groups in the mean change from baseline to week 12 was -0.98 (95% CI, -1.32 to -0.64; P<0.001). A significantly larger percentage of patients receiving BBUP than placebo had pain reductions ≥30% and ≥50% (P<0.001 for both). In the double blind portion of the study, the only adverse event reported more frequently with BBUP than placebo and in ≥5% of patients was vomiting (5.5% vs 2.3%). These findings demonstrate the efficacy and tolerability of BBUP in opioid-experienced patients taking around-the-clock opioid treatment for CLBP.
- Buprenorphine Initiation and Linkage to Outpatient Buprenorphine do not Reduce Frequency of Injection Opiate Use Following Hospitalization. [Journal Article]
- J Subst Abuse Treat 2016 Sep.:68-73.
Buprenorphine has established effectiveness for outpatient treatment of opioid use disorder. Our previously published STOP (Suboxone Transition to Opiate Program) trial showed that buprenorphine induction, stabilization, and linkage to outpatient treatment in opioid-dependent inpatients (injection and non-injection drug users) decreased illicit opioid use over 6months. The present study was a planned subgroup analysis of injection opiate users from STOP.To determine if inpatient buprenorphine initiation and linkage to outpatient buprenorphine reduce injection opiate users' frequency of injection opiate use (IOU).Inpatient injection opiate users at a safety-net hospital were randomized to buprenorphine linkage (induction, stabilization, bridge prescription, and facilitated referral to outpatient treatment) or detoxification (5-day inpatient buprenorphine taper). Conditional fixed-effects Poisson regression was used to estimate the effects of intervention on 30-day (self-report) at 1, 3, and 6months, measured using 30-day timeline follow-back. The secondary outcome was linkage effectiveness, measured as % presenting to initial outpatient buprenorphine visits after hospital discharge.Analysis was limited to persons (n=62 randomized to detoxification and n=51 to linkage) with baseline IOU. There were no significant differences in age, ethnicity, or baseline IOU frequency. At follow-up, linkage patients (70.6%) were significantly more likely (p<0.001) to present to initial buprenorphine visits than detoxification patients (9.7%). However, there was no significant between group difference in the rate of IOU at 1- (IRR=0.73, p=0.32), 3- (IRR=1.20, p=0.54), or 6-month (IRR=0.73, p=0.23) follow-ups. Using person-day analysis, participants self-reported IOU on 5.8% of follow-up days in which they used prescription buprenorphine and 37.5% of non-buprenorphine days. Using a generalized estimating equation, the estimated odds of IOU was 4.57 times higher (p<0.001) on non-buprenorphine days.Despite STOP's success in linking patients who inject opiates to outpatient buprenorphine, the intervention did not significantly decrease their IOU frequency. Injection opiate users will require a more intensive protocol to sustain outpatient buprenorphine treatment and decrease injection with its attendant risks.
- Hepatic Safety of Buprenorphine in HIV-Infected and Uninfected Patients With Opioid Use Disorder: The Role of HCV-Infection. [Journal Article]
- J Subst Abuse Treat 2016 Sep.:62-7.
Individuals with HIV and hepatitis C (HCV) infection, alcohol use disorder, or who are prescribed potentially hepatotoxic medications may be at increased risk for buprenorphine (BUP) associated hepatotoxicity.We examined a cohort of HIV-infected and uninfected patients receiving an initial BUP prescription between 2003 and 2012. We compared changes in alanine and aspartate aminotransferases (ALT and AST) and total bilirubin (TB) stratified by HIV status. We identified cases of liver enzyme elevation (LEE), TB elevation (TBE), and conducted chart review to assess for cases of drug induced liver injury (DILI) and death. We examined associations between age, sex, race, HIV-infection, HCV-infection, alcohol use disorder, and prescription of other potentially heptatotoxic medications with the composite endpoint of LEE, TBE, and DILI.Of 666 patients prescribed BUP, 36% were HIV-infected, 98% were male, 60% had RNA-confirmed HCV infection, 50% had a recent diagnosis of alcohol use disorder, and 64% were prescribed other potentially hepatotoxic medications. No clinically significant changes were observed in median ALT, AST and TB and these changes did not differ between HIV-infected and uninfected patients. Compared with uninfected patients, HIV-infected (OR 7.3, 95% CI 2.1-26.1, p=0.002), HCV-infected (OR 4.9 95% CI 1.6-15.2, p=0.007) or HIV/HCV co-infected patients (OR 6.9, 95%CI 2.1-22.2, p=0.001) were more likely to have the composite endpoint of LEE, TB elevation or DILI, in analyses that excluded 60 patients with evidence of pre-existing liver injury. 31 patients had LEE, 14/187 HIV-infected and 17/340 uninfected (p=0.25); 11 had TBE, including 9/186 HIV-infected and 2/329 uninfected (p=0.002); 8 experienced DILI, 4/202 HIV-infected and 4/204 uninfected (p=0.45). There were no significant associations with alcohol use disorder or prescription of other potentially hepatotoxic medications after adjustment for HIV/HCV status.Liver enzymes and TB are rarely elevated in HIV-infected and uninfected patients receiving BUP. Risk of hepatotoxicity was greater in individuals infected with HIV, HCV, or HIV/HCV co-infection, who may benefit from increased monitoring.