Feasibility Study of Oral Naloxone for Treatment of Methadone-induced Constipation

Background and rationale Opioid-induced constipation is the most common side effect of opioid therapy - depending on the settings up to 90% of patients taking opioids experience constipation with the most conservative estimate among MMT patients being 30%. Currently, the recommended treatment for opioid-induced constipation includes a combination of stool softeners, stimulants and osmotic laxatives - increased gastrointestinal secretions result in increased volume and softness of fecal masses, and more intense peristalsis promotes bowel voiding. The effectiveness of existing treatments for opioid-induced constipation is limited - they are effective in approximately 50% of cases, often have side effects such as abdominal cramping and diarrhea and, most importantly, do not address the pathobiological basis of opioid-induced constipation. Opioids in general and methadone in particular act on peripheral opioid receptors located in myenteric and submucosal plexus and cause relaxation of longitudinal and increased tone of inner circular smooth muscles as well as decreased gastrointestinal secretions that in turn result in constipation. The most logical therapeutic approach to the treatment of opioid-induced constipation in MMT would be using opioids that cause selective local reversal of μ-opioid activation with a peripherally-acting opioid antagonist such as naloxone, which when administered orally does not have systemic effects due to extremely low oral bioavailability.

Objectives The primary objective is to evaluate the effectiveness of a combination of methadone and naloxone in 50:1 for treatment of opioid-induced constipation in MMT patients. The secondary objective of the study is to assess the likelihood of development of opioid withdrawal symptoms in MMT patients who receive combination of methadone and naloxone compared to those who receive methadone only.

Design Study has a double-blind placebo-controlled crossover design: following signing informed consent and initial assessment 20 subjects who meet eligibility criteria will be randomized into one of two groups: group A will receive combination of methadone and naloxone in a ratio of 50:1 shown to be safe and effective in other trials during week 1 of the study and methadone only during week 2 of the study. Group B will receive methadone only during week 1 of the study and combination of methadone and naloxone in a ratio of 50:1 during week 2 of the study. Thus, all participants will receive combination of methadone and naloxone for one week and methadone alone for one week. Neither study participants, nor the pharmacists observing the doses, nor study personnel will know if naloxone is added to subjects' methadone preparations. Allocation to Group A or Group B will be done by random assignment. The pharmacy research medication management service will prepare the randomization code such that there will be a balanced assignment after every 4 subjects. Bowel functioning will be assessed quantitatively primarily using the Bowel Function Index (BFI) at initial assessment and at the end of weeks one (day 8) and two of the study (day 15). Also data on the number of complete spontaneous bowel movements (CSBMs), their temporal relationship to medication administration and outcome will be collected every day prior to administration of the next dose of methadone. In addition to parameters of bowel functioning Subjective Opiate Withdrawal Scale (SOWS) will be administered daily in order to assess potential opioid withdrawal symptoms.

Statistical Methods/Data Analysis Primary endpoint of the study is the reduction of constipation symptoms severity as measured by the difference between BFI scores taken after one week of receiving combination of methadone and naloxone and after one week of receiving methadone only. Secondary endpoint of the study is the occurrence of opioid withdrawal symptoms as measured by the difference between the mean SOWS scores taken daily during each of two weeks of the study. Paired t-test will be used to compare BFI and mean number of CSBMs between the weeks of treatment with a combination of methadone and naloxone and methadone alone as well as to compare average SOWS scores between the weeks of treatment with a combination of methadone and naloxone and methadone alone.