Introduction
A reexamination of the clinical principles involved in the initiation, continuation, and discontinuation of long-term opioid therapy (LTOT) for chronic pain is long overdue, especially in the context of an unrelenting opioid overdose crisis in United States (US) that is believed to have originated partly from excessive LTOT prescribing. LTOT reestablished itself as a prevalent treatment of non-cancer chronic pain in the late 1980s and the subsequent decades after the success of opioids in hospice care among cancer patients.1 This resurgence of popularity of LTOT was based on few clinical assumptions: 1) regular repeated use of opioids – powerful short-term analgesics –would provide sustained pain reduction for people with chronic pain, which would in turn provide sustained improvement in individual suffering and function, 2) opioid dependence and tolerance are expected physiological effects of LTOT that are benign in the absence of opioid use disorder (OUD) or addiction, 3) LTOT is largely safe and serious adverse effects like overdose, respiratory failure and addiction are rare and avoidable, and 4) opioid describing is safe and easy when indicated. Our clinical experience with LTOT over the past decades has suggested that none of these assumptions are valid.
By the 2010s, anecdotal clinical evidence started to emerge that many patients on LTOT develop a paradoxical pain syndrome whereby both continuation and discontinuation of LTOT was associated worsening pain and function instead of the commonly expected improved pain control and function. 2-4 Consistent with this clinical observation and contrary to the clinical assumptions justifying the therapeutic use of LTOT in chronic pain, up to two-thirds of patients on LTOT reported poor pain control, function and overall health,5,6 and LTOT was associated with declining pain control and function over 2 years of follow up in large observational studies.7 Recent clinical trials reported that while LTOT may have modest short-term benefits, it is not associated with clinically meaningful longer term benefits.8-10Contrary to previous assumptions, more recent clinical trial data have also suggested that opioids are not superior to placebo or non-steroidal anti-inflammatory agents in providing effective pain control or improved function even with common acute or sub-acute painful conditions like kidney stones or low back and neck pain.11-13 It is now well recognized that LTOT is not as safe as previously assumed and is associated with significant adverse effects including overdose and all-cause mortality.10,14-17 Although OUD or opioid addiction is uncommon among those on LTOT, it is not rare, with about 5% on LTOT in pain clinics developing OUD. 18,19Thus, the available clinical experience and data suggest that LTOT does not seem to provide consistent analgesia or improvement in function for most patients and may be associated with increased risk and a paradoxical worsening of pain and function among many.
It is well accepted that physiological opioid dependence without addiction/OUD is unavoidable after a few months on LTOT. It is commonly assumed that opioid deprescribing, the presumed primary option in treatment of ineffective and unsafe LTOT, is an easy option for many dependent on LTOT 10,20; however, qualitative studies report that opioid tapering is incredibly challenging for many such patients due to worsening pain and suffering from withdrawal.21-23 Consistent with this, results of observational studies have suggested that many patients dependent on LTOT do not want to come off opioids even when reporting worsening pain or even when faced with life threatening complications like overdose.6,24 In one study, 90% of people who suffered opioid related non-fatal overdose were restarted on opioids in the next year, demonstrating the difficulty in deprescribing.24 It is also commonly presumed that LTOT deprescribing is associated with significant benefits and a reduction of opioid related risks.10,20 However, systematic reviews have failed to reveal any substantial evidence demonstrating significant benefits or reduced risks associated with LTOT deprescribing.25,26 In fact, over a dozen recent observational studies have shown that opioid deprescribing is associated with an escalation of several types of opioid related risks including overdose, suicides, illicit opioid use, mental health destabilization, disruption of care relationships with provider, hospitalizations and even all-cause mortality.27-39 These risks appear to persist for months to years and risk does not appear to be diminished even with a slower taper, a commonly suggested solution to the harms of opioid deprescribing. 27-39 Thus, clinical experience and empirical data suggest that opioid dependence associated with LTOT is often not a benign state and opioid deprescribing is often difficult, ineffective, and risky among those with physiological dependence from LTOT and these adverse effects can persist for several years.
Despite all these limitations, LTOT is still often trialed among patients with debilitating chronic pain after other options have failed because of a shared hope among patients and providers that the short-term benefit will persist. In the absence of effective alternative short-term “pain medications,” opioids will continue to be used for the foreseeable future in several clinical situations where pain control is essential for clinical stabilization, treatment participation and acute functional recovery (e.g. recovery from severe physical trauma or extensive surgeries). Many of these patients could require LTOT to maintain their recovery journey. In addition, millions of patients who are already prescribed LTOT (i.e., “legacy” patients) need continued care as de-prescribing LTOT could be ineffective and risky. This opioid-induced pain crisis is a significant problem in US and often eclipsed by or confabulated with the opioid addiction crisis. About 14 million US adults were estimated to receive LTOT in 2014, declining to about 7 million by 2019 after the rise in popularity of opioid tapering following the 2016 CDC guidelines on opioid prescribing for chronic pain. 40-42 As a result, millions of US adults were left to cope with the adverse effects of opioid deprescribing that is often not recognized or treated as a valid clinical entity.43-45 In short, we cannot deprescribe our way out of the enormous clinical problem created by excessive LTOT prescribing over several decades.
The current conceptualization of LTOT as a long-term analgesic therapy with occasional side effects of overdose, misuse, and addiction and inevitable but benign and easily resolvable physiological opioid dependence appears to be an unjustifiable framework. The enormous opioid pain crisis that leaves millions of US adults in severe pain and disability– whether they are continued on LTOT or deprescribed– raises the need for a more scientific conceptualization of the role of opioids and LTOT to guide safe and effective LTOT use and deprescribing. To address this urgent need, we first provide a comprehensive review of the neurobehavioral mechanisms involved in opioid pain relief, explanations for the paradoxical worsening of pain and disability in LTOT continuation and persistent clinical worsening with deprescribing. We further suggest a detailed clinical approach to safe and effective LTOT use and treatment of ineffective or unsafe LTOT based on the above theoretical explanations for short- and long-term effects of opioids pertinent to pain treatment. We hope such a reexamination of clinical principles in LTOT will improve collaboration with patients facing the LTOT clinical conundrum or considering LTOT as an option and will help them move forward in the path to functional recovery.
A plain language description of common terminologies used in the next section is provided in Box 1.
———————–Start Box————————