Treating Opioid-Dependent Patients with OAT

Pharmacology Watch

A Perspective article in the Jan. 17 Annals of Internal Medicine reviews pain management in patients with a history of opioid addiction who are receiving opioid agonist therapy (OAT) with maintenance methadone or buprenorphine. These patients present unique challenges that frequently result in suboptimal treatment of acute pain.

The authors provide an excellent review of these challenging patients and point our 4 common misconceptions: 1) Maintenance opioids provide analgesia—not only is this not the case, but OAT may reduce the effectiveness of standard pain relief measures; 2) Opioids for analgesia may result in addiction relapse—there is no evidence that treatment of acute pain triggers relapse; 3) The additive effects of opioid analgesics and OAT may cause respiratory and CNS depression—tolerance to the respiratory and CNS effects of opioids develops rapidly and is not exacerbated by acute therapy; 4) Reporting pain is drug-seeking behavior—as long as there is clinical evidence of pain, or an acute injury, pain may be safely treated. Drug seeking and manipulation is more likely characterized by vague reports of long-term pain than requests for short term pain relief. Plus, patients on OAT are less likely to experience euphoria associated with coadministered opioids, so there is less incentive to drug seek.

The authors provide specific pain treatment recommendations for patients on methadone and buprenorphine. They conclude, "Addiction elicits neurophysiologic, behavioral, and social responses that worsen the pain experience and complicate provision of adequate analgesia. These complexities are heightened for patients with opioid dependency who are receiving OAT, for whom the neural responses of tolerance or hyperalgesia may alter the pain experience. As a consequence, opioid analgesics are less effective; higher doses administered at shortened intervals are required. Opioid agonist therapy provides little, if any, analgesia for acute pain. Fears that opioid analgesia will cause addiction relapse or respiratory and CNS depression are unfounded. Furthermore, clinicians should not allow concerns about being manipulated to cloud good clinical assessment or judgment about the patient's need for pain medications. Reassurance regarding uninterrupted OAT and aggressive pain management will mitigate anxiety and facilitate successful treatment of pain in patients receiving OAT" (Alford DP, et al. Ann Intern Med. 2006;144:127-134).

Long-Term Effects of Warfarin Use

Warfarin use may be associated with osteoporosis and fractures in men, but not women, with atrial fibrillation, according to new study. In a retrospective cohort study of Medicare beneficiaries with atrial fibrillation in United States, 4461 patients on long-term warfarin therapy were compared to 7587 patients who were not prescribed warfarin. The adjusted odds ratio of fracture was 1.25 in patients who took warfarin (95% CI, 1.06-1.48). The odds ratio for men was 1.63, and a nonsignificant 1.05 for women. In patients who were prescribed warfarin for less than one year, the risk of osteoporotic fracture was not increased significantly. The authors speculate that since warfarin blocks vitamin K dependent clotting factors, it may also block vitamin K dependent osteocalcin and other bone matrix proteins. Interestingly, use of beta blockers reduced the risk of fracture in this population. The authors conclude that long-term use of warfarin was associated with osteoporotic fractures in men with atrial fibrillation, and that beta-blockers may be somewhat protective (Gage BF, et al. Arch Intern Med. 2006;166:241-246).

Statins’ Multiple Benefits

Mounting evidence suggest that statins have benefits beyond their ability to lower LDL cholesterol. Multiple studies show that statins reduce inflammation in patients without heart failure. Now, 2 new studies suggest that they also reduce inflammation in patients with heart failure. In a study from Emory University, 108 patients with nonischemic heart failure were randomized to atorvastatin 20 mg per day or placebo. Inflammatory markers such as C reactive protein, interleukin-6, and TNF-alpha were all reduced in the atorvastatin group. Atorvastatin treated patients also showed an improvement in LVEF from 0.33-0.37 over one year (P = 0.01) (Sola S, et al. J Am Coll Cardiol. 2006;47:332-337).

A second study, from Harvard, in patients with heart failure showed that atorvastatin 10 mg/ day led to an 8% reduction in TNF receptor 1, a 37% reduction in C reactive protein, and a 17% reduction in endothelin-1 (Mozaffarian D, et al. Am J Cardiol. 2005;96:1699-1704). Atorvastatin may also have anti-thrombotic effects in patients with unstable angina according to a study from Greece. Forty-five patients with normal cholesterol levels and unstable angina were randomized to 10 mg of atorvastatin or placebo, starting right after hospital admission and continuing for 6 weeks. After one week of treatment circulating levels of anti-thrombin III, factor V, and von Willebrand factor were all significantly reduced in the atorvastatin group (Tousoulis D, et al. Int J Cardiol. 2006;106:333-337).

FDA Actions

The FDA has approved the first inhaled insulin for the treatment of adults with type I and type 2 diabetes. Inhaled insulin, a powder form of recombinant human insulin, has been in development for over 10 years, and has been the subject of intense scrutiny by the FDA. Concerns over long-term safety, particularly in people with underlying lung disease, has delayed approval, and safety in children and teenagers is still under investigation. Inhaled insulin is delivered through a device that is significantly larger than an asthma inhaler and, even folded, is the size of a flashlight. A blister pack of insulin powder is inserted into the device, which is then triggered. It is not to be used by smokers or people who quit smoking within last 6 months, and is not recommended for people with asthma, bronchitis, or emphysema. The FDA also recommends pulmonary function testing prior to starting inhalation therapy, and every 6 to 12 months thereafter. Although the product is approved for treatment of both type I and type 2 diabetes, fewer than 30% of type I diabetics achieve adequate control with inhaled insulin alone. Inhaled insulin is a joint effort by Pfizer, Sanofi-Aventis, and Nektar Therapeutics. It will be marketed under the trade name Exubera.

The FDA has approved an intravenous form of Ibandronate that can be administered every 3 months for the treatment of postmenopausal osteoporosis. The 3 mg dose is injected intravenously over 15 to 30 seconds by a healthcare professional. The drug is an option for women who cannot take pills or are unable to sit upright for 30 to 60 minutes after taking an oral bisphosphonate. Efficacy with the injectable form of ibandronate was better than once-a-day oral dosing of Ibandronate 2.5 mg in a study of over 1300 women with osteoporosis. Intravenous and oral forms of the drug were equally well tolerated. The FDA is recommending measurement of serum creatinines prior to administration each dose. Ibandronate is also approved is a 2.5 mg once a day oral dose and a 150 mg monthly oral dose. All 3 formulations are marketed as Boniva.

Berlex's combination estradiol-levonorgestrel patch (Climara Pro) has been approved for the indication for prevention of postmenopausal osteoporosis in women with an intact uterus. The patch was previously approved for the indication of moderate to severe vasomotor symptoms associated with menopause. The osteoporosis indication was based on a 2-year, double-blind, randomized trial that showed that the estradiol-levonorgestrel patch was associated with significant maintenance of bone density compared to placebo.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: