Relative effectiveness The analgesic efficacy of opioids for treating acute pain has been known for centuries and they continue to be reliable agents for moderate-to- severe acute pain, although they are not without risks. But the evidence for opioid efficacy for acute pain cannot be extended to chronic pain with a few exceptions that are discussed below. Neuronal and physiologic adaptations to long-term opioid use can result in reduced analgesic effectiveness, or even, paradoxically, increased pain or sensitivity to pain. 72 Opioid-induced hyperalgesia is different pharmacologically from the phenomenon of opioid tolerance, although both can lead to an increased need for opioids and disentangling the two, clinically, can be difficult. 73 For chronic pain, the evidence that opioids reduce pain and improve function more than placebo is relatively weak. A 2018 systematic review and meta-analysis of 96 trials comparing various opioids vs. placebo or non-opioid analgesics in 26,169 patients with chronic noncancer pain found that opioids may slightly reduce pain and increase physical functioning compared to placebo, but not compared to non-opioids. 12 In 76 trials comparing opioids vs. placebo with follow-up ranging from 1 to 6 months, the reduction in pain scores with opioids (on a 10-point scale) was only 0.69 points, which is below the generally-accepted 2-point minimum clinically important difference for pain. Physical function scores (on a 100-point scale) improved with opioids by 2.04 points, which, again, may not be clinically important. The risk of vomiting with opioids, however, was more than 4 times higher than with placebo. 12 The same meta-analysis compared opioids to non-opioid analgesics including NSAIDs, TCAs, anticonvulsants, and synthetic cannabinoids. No significant differences were found in physical functioning scores for any of the comparisons, and no significant differences were found in pain scores for comparisons with NSAIDs, TCAs, or cannabinoids. 12 Exceptions: chronic opioid use in limited patient subsets Sickle cell disease as an example for which chronic opioid therapy may be appropriate in some patients. The risk for opioid death in patients with sickle cell disease comprises a small fraction of the total number of opioid-related deaths. From 1999 through 2013, there were 174,959 documents deaths attributed to opioid use. Of these 174, 959 deaths, 95 were patients with sickle cell disease (0.05%). 74 The pain experienced by patients includes both acute and chronic aspects through multiple mechanisms that are not completely understood. The American Society of Hematology 2020 guidelines endorses the use of
chronic opioid therapy for patients with sickle cell disease with pain that is refractory to multiple other treatments using the lowest effective dose and with regular monitoring. 75,76 Opioid formulations Prescription opioids are available in immediate- release and extended-release/long-acting (ER/ LA) formulations. Immediate-release agents are recommended in opioid-naïve patients and for all acute pain conditions, with ER/LA agents reserved for patients or conditions in which the longer duration of action and smoother pharmacodynamics are preferred. 31 A trial comparing immediate release to an ER/LA opioid did not find evidence that the continuous, time-scheduled use of ER/LA opioids was more effective or safer than intermittent use of the immediate-release opioid. 71 According to the FDA, ER/LA opioids should only be used for patients who tolerate 60 morphine milligram equivalents per day (MMED) for at least one week. 78 Efforts to create formulations with lower risks of abuse have met with limited success. For example, ER Oxymorphone was removed from the market after reports of intravenous abuse of the oral formulation. 79 Abuse-deterrent or tamper- resistant formulations do not prevent patients from developing opioid dependence, opioid use disorder, or simply taking too much of an opioid by mouth. 80,81 BEFORE MOVING ONTO THE NEXT SECTION, PLEASE COMPLETE CASE STUDY 2 ON THE NEXT PAGE. Atypical opoids: tramadol and tapentadol Tramadol and tapentadol are mu receptor agonists and norepinephrine reuptake inhibitors. Their mechanisms of action are unknown, but their analgesic effects are similar to morphine. Patients taking tramadol should be monitored for nausea, vomiting, constipation, and drowsiness, all of which are similar to side effects with opioids. 82 There is potential risk of serotonin syndrome when tramadol is combined with SSRIs, SNRIs, or tricyclic antidepressants. 83 As noted above, tramadol is classified as Schedule IV, which has led some to view it as less potent or safer than other opioids. The 2016 National Survey on Drug Use and Health, however, found that 1.7 million people in the U.S. aged > 12 years reported misusing tramadol products (e.g., Ultram, Ultram ER, Ultracet) in the previous year. 71 In addition, a 2019 cohort study of 88,902 patients with osteoarthritis showed increased risks of death at one year compared to NSAIDs naproxen, diclofenac, and celecoxib. 84
Abrupt cessation of tramadol is associated with opioid withdrawal, restlessness, and drug cravings (similar to those associated with other opioids) as well as hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and numbness/tingling in extremities (which are less typical of other opioids). 85 Tapentadol is FDA-approved for treating neuropathic pain associated with diabetic peripheral neuropathy, although it is also used for musculoskeletal pain. A 2015 Cochrane review of 4 randomized trials with 4,094 patients with osteoarthritis or back pain found modest reductions in pain with tapentadol vs. placebo. 86 Problematic opioid use Although evidence for the long-term effectiveness of opioids for chronic pain is weak, evidence for opioid-related harms is abundant and strong. In a 2007 study assessing behaviors indicative of opioid misuse, many patients in primary care practices reported having engaged in aberrant behaviors with opioids one or more times (Table 2). 9 It is important to recognize and differentiate problematic use from adverse side effects of opioids. For instance, tolerance and opioid withdrawal occur with long term use of prescribed opioids. Clinicians should be able to differentiate this from problematic use. Among adults without a prescription, 41% obtained prescription opioids from friends or relatives for their most recent episodes of misuse. 87 For prescription opioids, long-term therapy is associated with an increased risk in accidental overdose and death. A retrospective study including 9,940 patients who received three or more opioid prescriptions within 90 days for chronic pain between 1997 and 2005 found that annual overdose rates rose significantly as doses exceeded 50 MMED (Figure 4). 88 Combining opioids with sedating drugs such as benzodiazepines or alcohol increases the risk of respiratory depression and overdose death. 34 Benzodiazepines have been linked with overdose fatalities in 50-80% of heroin overdoses, and 40- 80% in methadone-related deaths. 34,89 Patients prescribed benzodiazepines who are being initiated on opioids should have their benzodiazepine tapered and discontinued whenever possible. For patients being co-managed by mental health professionals, coordinate a plan regarding continuing or tapering benzodiazepines in the setting of opioid co-prescribing.
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