Chronic Pain: Opioid Tapering

Many clinical guidelines aimed at improving safety of long-term opioid therapy for chronic pain recommend discontinuing opioids under certain circumstances, including failure to meet treatment goals or development of problematic opioid use. Knowledge about opioid tapering is limited, however, in part because there are no validated protocols tailored to adults with chronic pain. This is important because knowledge gaps about opioid tapering may represent a critical barrier to delivering optimal and possibly life-sustaining care to people receiving long-term opioid therapy.

The purpose of this review is to provide pragmatic information about opioid tapering in adults with chronic pain for use in daily clinical practice. This article has a chronic pain focus; thus, the content is not intended to be applicable to individuals with opioid use disorder (OUD). First, we provide a concise review of opioid pharmacology including mechanisms of analgesia, tolerance, and acute withdrawal. Next, we discuss key clinical indications for opioid tapering and risks associated with nonconsensual discontinuation of long-term opioid therapy. We also address pretaper planning, approaches to developing opioid taper schedules, and pharmacologic management of acute opioid withdrawal and end with a discussion of the clinical outcomes of opioid tapering in adults with chronic pain.

Opioid Pharmacology

Opioid Analgesia

Opioids bind to a 7-transmembrane G-protein coupled receptor (GPCR) distributed throughout the central nervous system.¹ The μ, δ, and κ opioid receptors, with distinct functional characteristics have been identified (Table 1).² The μ opioid receptor is primarily responsible for the clinical analgesic effects of opioids. Receptor activation results in cell membrane hyperpolarization, adenylate cyclase inhibition, and downregulation of cyclic adenosine monophosphate (cAMP).¹ This intracellular cascade works to inhibit the release of key neurotransmitters involved in nociception, including substance P, GABA, acetylcholine, norepinephrine, and dopamine.

Opioid Tolerance

Opioid tolerance is characterized by the temporal loss of analgesia to a recurring opioid dose and is manifest clinically by the need for dose escalation in order to achieve the desired level of analgesia. A complex constellation of adaptive neurobiologic processes coalesce to produce opioid tolerance, including downregulation of opioid receptors, desensitization of coupling between opioid receptors and intracellular second messenger systems with adaptive upregulation of cAMP, and adaptations in synaptic and neural circuitry function.^3,4

Opioid Withdrawal

Although the signs and symptoms of opioid withdrawal (Table 2) are mediated by multiple neural adaptations in response to long-term exposure to exogenous opioids,^3,4 the preponderance of acute withdrawal symptoms are caused by excess norepinephrine release from opioid-sensitive cells in the locus coeruleus. Acute opioid exposure is associated with an initial downregulation of cAMP in the locus coeruleus and reduced norepinephrine release. After long-term exposure, however, the cAMP pathway is adaptively upregulated, which restores baseline norepinephrine release. Abrupt opioid cessation unmasks the adaptive upregulation of cAMP in the locus coeruleus leading to excess norepinephrine release and the signs and symptoms of acute opioid withdrawal.

Nonconsensual Opioid Tapering

Indications for Opioid Tapering or Dose Reduction

The clinical indications governing opioid discontinuation can be generally organized into 4 categories (Table 3).^5,6 The first category includes an individual’s request to discontinue or reduce the opioid dose; the clinician should explore the rationale for this decision with the patient and document it appropriately. Another related indication could be that the goals of opioid therapy were met. This scenario can be encountered when long-term opioids are used to facilitate a prolonged course of physical rehabilitation following trauma or other major medical or surgical treatments. The second category includes clinical evidence that long-term opioid therapy did not meet anticipated treatment goals. Failure to meet anticipated treatment goals encompasses patients who experience deterioration in physical and emotional functioning in the context of long-term opioid therapy.^7,8 The third category includes changes in a patient’s baseline health status that can increase their risks of adverse effects. Although this could involve deterioration in the capacity to metabolize opioids, other important considerations include the development of central nervous system diseases that could increase the risk of opioid-induced delirium. The final category includes patients who develop signs of opioid misuse or OUD or engage in drug diversion.

Risks Associated With Nonconsensual Opioid Tapering

Awareness of the potential risks associated with nonconsensual discontinuation of long-term opioid therapy is paramount before initiating opioid tapering.⁵ Mutual agreement between a patient and clinician to taper opioids, termed consensual tapering, is generally safe and effective.⁹ Nonconsensual tapering occurs when the patient does not consent or agree to taper opioids. The risks associated with this clinical practice include failure to complete the taper and termination of care, increased use of hospital and emergency medicine resources, increased rate of fatal overdose, worsening anxiety and depressive symptoms, and increased rate of suicidal ideation.^10-12 The risks of nonconsensual tapering could be influenced by individual patient factors (eg, OUD, opioid misuse, or drug diversion) that precipitated the decision to taper opioids. Regardless, nonconsensual tapering should be avoided,¹³ but if this is not possible, efforts should be made to ensure the patient is in a safe and protected environment.

Planning, Schedules, and Withdrawal Management

Planning

A person-centered approach to pretaper planning centers on identifying a specific person’s risks, barriers, facilitators, and benefits of opioid tapering.¹⁴ In a qualitative study that used in-person, semistructured interviews, individuals with chronic pain espoused a low perceived risk of overdose, and perceived risk of pain was greater than the risk of overdose. Although providing education about risk of overdose is important, these data suggest that outcomes unique to each patient should be identified, and patients should be reassured that all feasible efforts will be made to manage pain during and after the taper.

Juxtaposed against the risk of inadequate pain control, perceived barriers to opioid tapering include pessimism about the effectiveness of nonopioid pain care after tapering and past experience with opioid withdrawal symptoms. Patient-specific experiences with nonopioid pain care (eg, pharmacotherapy, interventional treatment, or behavioral interventions) should be carefully explored to identify modalities with the greatest levels of combined effectiveness and patient acceptability.

Important facilitators of opioid tapering include social support, practitioner accessibility, and perceived trust in the clinician. These data suggest that identifying social supports prior to initiating tapering is important, and involvement of a peer mentor should be considered. These data also suggest that a key goal throughout the pretapering planning period is to develop a strong professional alliance with the patient.

In this qualitative study, patients who were able to taper chronic opioids endorsed improved quality of life.¹⁴ Thus, anticipated engagement in specific activities or changes in specific functional domains should be identified before initiating opioid tapering.

Opioid Taper Schedules

To date, evidence-supported taper schedules from randomized clinical trials have not been reported. Percent-based dose reductions, however, have widespread support and are used clinically.^6,9 Although multiple factors may influence the rate of tapering, the decision to implement a slow or rapid taper is generally dependent on the indications for tapering. Slow tapers are usually consensual, and the temporal course is secondary to the anticipated goals of tapering. In these scenarios, flexible dose reductions of 5% to 10% can occur weekly, every other week, or every month depending on the individual’s response to the taper schedule. The amount and frequency of dose reductions should be structured to ensure that the goals of tapering, as identified in the pretaper planning sessions, are accomplished. Under these favorable conditions, signs of acute opioid withdrawal are typically not encountered.

Rapid tapering is generally undertaken to protect patient safety and, in some circumstances, public safety. Rapid tapers can be consensual in patients who experience sudden changes in their health status, but rapid tapers are often nonconsensual. For example, individuals with opioid misuse or early signs of OUD may not recognize the risks posed by ongoing opioid use. Under these clinical circumstances, dose reductions of 10% every 2 to 3 days may be necessary. Among people taking more than 90 mg of daily morphine equivalents, an initial 30% dose reduction can be made without precipitating acute opioid withdrawal; however, the ensuing course of a rapid taper is generally associated with symptoms of opioid withdrawal.

Under extreme circumstances, abrupt and nonconsensual opioid cessation may be indicated in those with poorly or uncontrolled opioid use who pose an immediate threat to safety; active suicidal ideation, suicide attempt or overdose; progression of a nonopioid substance use disorder that poses an immediate threat to safety; and drug diversion or drug trafficking. Except for the rapid onset of severe mental health problems, a prodromal period of escalating aberrant behavior typically characterizes the majority of clinical scenarios warranting abrupt cessation. Early recognition is important because nearly 50% of all violent threats against clinicians in outpatient pain clinics are related to opioid management.¹⁵

Pharmacologic Management of Acute Opioid Withdrawal

The temporal onset of opioid withdrawal is dependent on the half-life of the opioid.^16,17 Symptoms of opioid withdrawal emerge within 12 hours of abrupt cessation of short-acting drugs (eg, oxycodone, hydrocodone, and fentanyl), peak between 36 and 72 hours, and abate within 7 to 10 days. For opioids with longer half-lives (eg, methadone), symptom onset occurs within 30 hours of abrupt cessation, peaks at 72 to 96 hours, and persists for 14 days or more. Use of higher doses of short-acting opioids for long periods are factors associated with greater severity of withdrawal symptoms.¹⁶

The pharmacologic management of acute opioid withdrawal is based on 2 related mechanisms. As discussed earlier in this article, long-term opioid therapy is associated with an adaptive upregulation of the cAMP pathway in opioid-sensitive noradrenergic neurons located in the locus coeruleus. Abrupt opioid cessation triggers a cAMP-mediated surge of norepinephrine that is responsible for acute opioid withdrawal. Treatment involves targeting the cAMP pathway via μ opioid-receptor agonism or inhibiting norepinephrine release from the locus coeruleus via presynaptic α-2 receptor agonism.¹⁸

μ Opioid Receptor Agonist. Buprenorphine is a highly potent μ opioid receptor partial agonist with a half-life of 31 to 33 hours. When used in the context of opioid tapering to mitigate withdrawal symptoms, sublingual buprenorphine can be substituted for the opioid being tapered. Buprenorphine should not be administered on an as-needed basis forwithdrawal symptoms because the drug will displace the opioid from the μ opioid receptor and precipitate acute withdrawal. The first dose of sublingual buprenorphine (2-4 mg) should be administered upon the emergence of mild-to-moderate withdrawal symptoms, which typically occur 12 to 14 hours after the last dose of a short-acting opioid.¹⁸ If withdrawal symptoms persist after 1 to 2 hours, a second dose of 2 to 4 mg is recommended. Depending on patient-specific factors, doses of 2 to 4 mg can be repeated every 6 to 8 hours for a total dose of 8 to 12 mg on the first day. On the second day, 4 mg can be administered every 6 to 8 hours and—after withdrawal symptoms resolve—buprenorphine can be tapered over 5 to 7 days.¹⁸

Buprenorphine substitution may be indicated for medically competent patients undergoing a rapid but consensual taper. Buprenorphine substitution, however, is most likely not indicated for nonconsensual tapers because a high level of adherence is generally required. Buprenorphine substitution may also be indicated for recalcitrant withdrawal symptoms in those undergoing a slow taper.

Confusion exists about the prescribing authority for buprenorphine. Buprenorphine is approved by the Food and Drug Administration (FDA) for treatment of acute pain, chronic pain, and OUD. When used to treat OUD, a waiver issued by the Drug Enforcement Administration¹⁹ is required but no waiver is needed to prescribe for pain or to use the drug to facilitate opioid tapering in the absence of OUD.

α-2 Adrenergic Receptor Agonists. Activation of presynaptic α-2 adrenergic receptors activates a negative feedback loop that inhibits norepinephrine release. Clonidine and lofexidine are α-2 receptor agonists widely used to treat opioid withdrawal.²⁰ Clonidine is FDA approved for hypertension and attention-deficit/hyperactivity disorder and used off-label for opioid withdrawal. For mild withdrawal, clonidine 0.1 to 0.2 mg every 6 to 8 hours is typical but severe symptoms may require 0.1 to 0.2 mg every 4 hours.¹⁷ In 2018, lofexidine was approved by the FDA for opioid withdrawal. Lofexidine is available as a 0.18 mg tablet and a typical dose regimen is 0.54 mg to 0.72 mg every 6 hours. Although the efficacy of clonidine and lofexidine for opioid withdrawal are similar, hypotension is more problematic with clonidine compared with lofexidine.²⁰

Supportive Medications. Supportive medications are commonly used to target residual symptoms of opioid withdrawal.^17,18 A variety of sleep aids are used for sleep disruption, including zolpidem, eszopiclone, trazodone, and low doses of tricyclic antidepressants. Myalgia, arthalgia, and other sources of musculoskeletal pain can be treated with acetaminophen and nonsteroidal anti-inflammatory drugs. Ondansetron and prochlorperazine are widely used for nausea, and loperamide can be used for diarrhea. Although opioid withdrawal is generally not fatal, deaths related to poor management of dehydration have been reported²¹; thus, hydration status of anyone with protracted withdrawal should be carefully monitored.

Beyond medications, wearable devices may assist with withdrawal symptoms.²² Aimed at delivering stimulation to peripheral cranial nerve bundles in the region of the ear, these devices have shown promise in reducing withdrawal symptoms, but prospective trials are needed to confirm the treatment effect.

Clinical Outcomes of Opioid Tapering

At least 2 systematic reviews suggest that opioid tapering is associated with improvements in pain and functionality. In the first systematic review that included 67 studies focusing on opioid reduction and discontinuation, significant improvements in pain, functioning and quality of life were reported.²³ In a second systematic review that included 20 studies, it was posited that pain improves or does not change following opioid tapering.²⁴ Improvement in pain after tapering was reported in 16 studies; pain was unchanged in 3 studies; and in a single study, pain was unchanged or improved in 97% of patients and worse in 3% following opioid tapering.

Following resolution of acute withdrawal symptoms, clinical investigators have described a constellation of persistent symptoms including hyperalgesia, high levels of negative affect, and anhedonia.²⁵ Individuals who experience this may have comorbid mood disorders, but they do not meet criteria for OUD and do not crave opioids. This clinical scenario has been termed complex persistent opioid dependence, and ongoing research is needed to identify effective treatments.²⁵

Summary

The pragmatic information and approaches set forth in this article are small steps toward optimizing opioid tapering in adults with chronic pain. However, a pressing need exists for ongoing research to develop, test, and disseminate effective opioid tapering protocols specifically tailored for adults with chronic pain.