Applying Best Practice Guidelines on Chronic Pain in Clinical Practice—Treating Patients Who Suffer From Pain and Addiction

Disclosure Statement

Dr. Heinzerling has received research support and study medication, but no salary, from Alkermes, Medicinova, and Denovo pharmaceuticals.

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” and chronic pain is defined as “pain that persists beyond normal tissue healing time, which is assumed to be 3 months.” An estimated 126.1 million United States (US) adults report some pain in the previous 3 months while 25.2 million (11.2%) report chronic pain. Costs to US society in medical expenditures and lost productivity from chronic pain are estimated to be $560–$635 billion, more than the yearly costs of heart disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion).

Opioid prescribing in the US increased dramatically since 1999 largely due to increased prescribing of opioids to treat chronic pain. Opioid prescriptions in the US peaked in 2010 at 782 morphine milligram equivalents (MME) per capita and then decreased to 640 MME per capita in 2015, although the 2015 US prescribing rate was still three times as high as 1999 and four times higher than the prescribing rate for Europe in 2015. The United States consumes 80% of all the opioids manufactured globally each year. The large increase in prescribing has occurred with little data to support the effectiveness of chronic opioid therapy for noncancer pain and an explosion of data regarding serious adverse effects of opioid therapy including fatal overdoses. Clinical trials of opioids for chronic low back pain have found short-term reductions in pain relative to placebo but have not assessed complications of chronic opioid therapy including opioid misuse, overdose, or addiction. Prevalence of prescription and illicit opioid use disorder have also increased, with 2 million Americans reporting misuse of prescription opioids and nearly 600,000 reporting heroin use disorder in 2015. Furthermore, paralleling the increase in opioid prescribing has been an equally dramatic increase in deaths due to opioid overdose. Drug overdose rates in the US tripled from 1999 to 2015, with 52,404 Americans dead from a drug overdose in 2015, of which 63% involved an opioid, compared to 16,849 overdose deaths in the US in 1999.

Pain, substance use disorders, and psychological conditions are commonly comorbid. Prevalence of pain among people receiving substance use disorder treatment ranges from 40% to 60%. Estimates of substance use disorders among chronic pain patients are highly variable ranging from 0.05% to 26% for opioid use disorder, from 3% to 48% for substance use disorders not restricted to opioids, and from 8% to 29% for opioid misuse. Anxiety and depression are also common among patients with chronic pain and are risk factors for prescription opioid misuse and overdose. Patients with chronic pain are four times as likely to have anxiety or depression than those without chronic pain and in a sample of patients on opioids for chronic pain, 37% had an anxiety disorder and 34% depression. Pain catastrophizing, a negative cognitive–affective response to anticipated or actual pain, is associated with increased risk of chronic pain, higher levels of pain intensity and interference, greater disability, and worse treatment outcomes. Higher levels of pain catastrophizing and pain-related anxiety are associated with lower heat pain threshold and tolerance in patients with chronic pain while pain catastrophizing, distress intolerance, depression, and anxiety are associated with prescription opioid misuse. Negative affect, a cluster of negative emotions and thoughts manifesting as high levels of depression, anxiety, and catastrophizing is common in chronic pain. Negative affect is associated with lower opioid analgesia, higher opioid doses, increased rates of opioid misuse, and increased risk for the development of opioid-induced hyperalgesia (OIH) among patients treated with opioids for chronic low back pain.

Recent research into the neurobiology of chronic pain has emphasized the affective and motivational dimensions of the chronic pain syndrome, the role of brain reward systems in pain chronification, and overlap between the brain areas involved in chronic pain and addiction. Pain is a multimodal subjective experience with both sensory and affective dimensions with different brain systems processing each of these dimensions. In particular, deficits in dopaminergic functioning similar to those found in addictive disorders have been found in chronic pain and the mesolimbic reward system plays a critical role in mediating the affective and motivational aspects of chronic pain and analgesia. In a series of neuroimaging studies, baseline structural and functional connectivity within the mesocorticolimbic system, not areas related to pain sensation, predicted the development of chronic low back pain among patients undergoing imaging at the onset of acute back pain. Of note, the same brain areas involved in affect and motivation that predict onset of chronic pain are also critically involved in addiction. Opioids relieve the affective aspect of pain, and the boost in mood some patients receive from opioids is rewarding. In light of the shared neurobiology underlying chronic pain and substance use disorders, it is not surprising that the dramatic increase in opioid prescribing for chronic pain has been accompanied by increases in opioid use disorder and overdose.

Clinicians and patients face multiple challenges and barriers to successfully treating pain in the context of substance use disorders. Many medications used for pain have an abuse liability and carry a risk of overdose especially when combined, including opioids, benzodiazepines, skeletal muscle relaxants, and gabapentinoids. Patients with active substance use problems prescribed pain medications may misuse the prescribed medications and/or combine them in a dangerous fashion with illicit drugs or alcohol. Patients with past substance use disorders in remission and their clinicians may have concerns that exposure to potentially addictive medications may trigger a relapse. While these are legitimate clinical concerns, patients also fear that addiction-related issues may result in their pain being undertreated leading to loss of trust, conflict, and breakdown of the doctor–patient relationship thereby further complicating treatment. Navigating these potential conflicts requires clinicians to strike a balance between acknowledging the patient's perspective and avoiding iatrogenic harm by emphasizing a collaborative and shared approach to decision-making.

In response to the US epidemic of opioid abuse and overdose, the Centers for Disease Control and Prevention issued guidelines for prescribing opioids for chronic pain. The guidelines strongly recommend against opioids for chronic noncancer pain, instead recommending nonpharmacologic and nonopioid pharmacologic therapy. If opioids are started for chronic pain the guidelines recommend avoiding dose escalation and keeping the dose to less than 50 morphine milligram equivalents (MME)/day. Doses ≥90 mg MME/day are high risk for overdose and should be avoided. Opioids and benzodiazepines should not be prescribed concomitantly due to synergistic overdose risk. If opioids are used for acute pain, the guidelines recommend limiting opioids to a short course of the lowest dose of an immediate-release opioid for 3 days or rarely as long as 7 days. Offering or providing medication-assisted treatment with approved medications, e.g., methadone, buprenorphine, and long-acting injectable naltrexone, along with behavioral treatment, for patients with opioid use disorder is also recommended.

While avoiding prescribing opioids in patients with substance use disorders may be the safest option, this is not possible or even clinically appropriate in all situations such as severe acute pain, surgical/procedural pain, cancer pain, end of life/palliative care, and even some cases of chronic noncancer pain. Tailoring treatment to each patient's needs to maximize potential benefits and mitigate risks is most likely to produce good clinical outcomes such as a reduction in pain and suffering while minimizing iatrogenic harms. Below, we review the evidence for a variety of pharmacologic and nonpharmacologic pain management treatments in patients with opioid use disorder as well as nonopioid substance use disorders. We aim to provide clinicians and patients with evidence with which to pursue a shared decision-making process aimed at identifying treatment plans to alleviate pain and suffering while mitigating risk of developing or worsening addiction.

Methadone

Methadone is a synthetic mu-opioid agonist with a long half-life (range 5–55 h) used as an analgesic and an approved treatment for opioid use disorder. In the US, physicians can prescribe methadone to treat pain but methadone maintenance treatment for opioid use disorder must be dispensed within the context of highly structured and regulated opioid treatment programs with once-daily supervised dosing aimed at minimizing the risk of methadone misuse or diversion. Evidence from multiple randomized clinical trials shows that methadone maintenance treatment for opioid use disorder reduces illicit opioid use and increases treatment retention relative to placebo and methadone retains patients in opioid use disorder treatment longer than buprenorphine. Although years of clinical experience support methadone's analgesic effects, the few studies of methadone for cancer and chronic pain have been small and of short duration finding methadone to be similar to morphine but with a greater risk of sedation. Methadone is an NMDA-receptor antagonist resulting in methadone's purported efficacy for chronic neuropathic pain although results of the small, low quality clinical studies of methadone for neuropathic pain are mixed.

There are several potential serious adverse effects with methadone. There is a risk of serious cardiac events with higher doses of methadone including QT prolongation, torsade de pointes, ventricular arrhythmias, and cardiac arrest and patients on doses ≥120 mg a day should be monitored with electrocardiograms and assessed for other pro-arrhythmic factors such as electrolyte abnormalities and concomitant prescription of HIV antiretrovirals. In the US, methadone prescribed for pain outside of methadone maintenance programs has been responsible for a disproportionate number of prescription overdose deaths, with methadone accounting for 2% of US opioid prescriptions in 2009 but approximately 30% of prescription opioid overdose deaths. Prescribing of methadone to patients with substance use disorders for pain outside of methadone maintenance programs should be approached with great caution due to the risk of accidental overdose especially if methadone is combined with other sedatives such as benzodiazepines or alcohol. The long and variable half-life of methadone combined with multiple possible drug-drug interactions contribute to the high risk of overdose with methadone and require that methadone be initiated at a low dose and titrated very slowly with clinical monitoring.

Chronic pain is common among methadone maintenance patients with prevalence from 50% to 60% compared to approximately 30% among adults in the US general population. Opioid-induced hyperalgesia (OIH) is clinically characterized by increasing pain intensity over time, pain spreading to other locations beyond the initial site of pain, and increased pain sensation in response to external stimuli, in the context of exposure to opioids. OIH has been demonstrated in animal models and following short-term, intra-operative use of opioids but whether chronic opioid use, such as with illicit opioid use, methadone maintenance, or chronic pain treatment, results in clinically meaningful hyperalgesia is less clear.

Studies have consistently found that methadone maintenance patients are hyperalgesic to experimental pain induced by the cold pressor test but studies have less consistently demonstrated hyperalgesia via electrical, thermal, or pressure pain stimulation. A few small studies found that history of chronic pain, but not methadone dose, was a significant predictor of pain threshold in methadone maintenance patients and additional studies examining the influence of methadone dose and chronic pain status on hyperalgesia in methadone patients are warranted. Heroin users were also hyperalgesic via cold pressor prior to starting methadone/buprenorphine treatment while abstinent heroin users are less hyperalgesic than those receiving methadone treatment suggesting that hyperalgesia results from ongoing opioid exposure and is not unique to methadone. In fact, hyperalgesia was similar among methadone maintenance patients and chronic pain patients treated with methadone or morphine.

OIH is thought to be mediated in part by activation of excitatory NMDA glutamate receptors. Methadone is an NMDA antagonist and how to rectify this with findings of OIH in methadone maintenance patients is not clear. Ketamine is an NMDA antagonist and reduces postoperative hyperalgesia but whether ketamine may be useful as an adjuvant to prevent or reduce hyperalgesia with methadone treatment has not been established. Dextromethorphan, also an NMDA-receptor antagonist, did not reduce hyperalgesia more than placebo in a randomized trial among methadone maintenance patients. Gabapentin significantly increased pain threshold and tolerance more than placebo in a small randomized clinical trial in a methadone maintenance treatment program, although nonadherent and nonopioid abstinent participants were excluded from the analysis and chronic pain status of the participants is not described.

Studies of hyperalgesia among methadone maintenance patients are limited by small sample size, observational designs, and inconsistent results using pain measures other than the cold pressor test. Prospective studies of hyperalgesia among chronic pain patients have conflicting results with some studies finding that prescription opioid use predicted the onset of hyperalgesia and others failing to find an effect. In a randomized, double-blind, placebo controlled trial, patients with chronic low back pain did not develop hyperalgesia after 1 month of morphine treatment although longer treatment and/or higher doses may be necessary for the development of OIH. Larger, prospective, well-controlled studies assessing the effect of methadone maintenance on hyperalgesia and the impact, if any, of hyperalgesia to experimental pain on important clinical outcomes, such as opioid relapse and quality of life, are needed.

Pain management in methadone maintained patients is complicated by cross-tolerance between methadone and other opioid analgesics such that high opioid doses may be needed to achieve analgesia. Also methadone's analgesic effects last 4–6 h and methadone for pain should be dosed two to three times daily as compared to once-daily methadone maintenance dosing. Strategies to address this include adding an additional short-acting opioid to the methadone or splitting the daily methadone dose into twice or thrice daily dosing and slowly titrating methadone to achieve analgesia. The addition of another opioid to methadone maintenance treatment must be done cautiously and in coordination with methadone maintenance dosing to reduce the risk of accidental overdose. There are no randomized trials addressing questions related to pain management during methadone maintenance treatment and the available studies are limited to small observational studies and case reports. A retrospective study found that providing additional analgesic methadone on top of the methadone maintenance dosing resulted in a reduction in pain scores among 53 patients with HIV and chronic pain undergoing methadone maintenance treatment. Additional methadone was titrated to approximately 200% of the initial methadone maintenance dose and was well tolerated and rates of heroin use were relatively low (13% opioid positive urine drug screens at 12 months). Cognitive behavioral therapy is effective for pain management, but many methadone program counselors are not trained or equipped to address pain and studies to integrate behavioral approaches to pain management within substance use counseling programs are needed.

Buprenorphine

Buprenorphine is a mu-opioid partial agonist that is approved by the US Food and Drug Administration (FDA) for treatment of opioid use disorder and pain. Buprenorphine is available in sublingual and buccal formulations of buprenorphine/naloxone and newly approved long-acting buprenorphine depot formulations for opioid use disorder as well as transdermal, buccal, and intravenous buprenorphine formulations approved for treating pain. The addition of naloxone to buprenorphine is to deter intravenous buprenorphine use as naloxone is poorly absorbed when administered sublingually but precipitates opioid withdrawal if buprenorphine/naloxone is injected. As a partial opioid agonist, buprenorphine has a ceiling effect for respiratory depression making it safer than methadone, although there is still a risk of overdose when buprenorphine is combined with sedatives such as benzodiazepines or alcohol. Risk of cardiac arrhythmias and QT prolongation with buprenorphine is much lower than with methadone. The improved safety profile and lower risk of misuse and overdose with buprenorphine relative to methadone led to the approval in the US of buprenorphine for the treatment of opioid use disorder in office-based settings by certified physicians as opposed to highly regulated and controlled methadone clinic settings. Buprenorphine reduces heroin use compared to placebo but may be less effective than high-dose methadone in cases of severe opioid use disorder.

Buprenorphine is more effective for treating chronic pain than placebo and similar in analgesic effect to full opioid agonists in multiple clinical trials for cancer pain and noncancer pain including low back pain, joint pain, and neuropathic pain. The majority of these studies evaluated transdermal and buccal buprenorphine formulations approved for pain as opposed to the sublingual buprenorphine/naloxone formulation approved for treating opioid use disorder, and few studies included patients with opioid addiction. In a large, multisite clinical trial (N = 653) of buprenorphine/naloxone treatment for prescription opioid use disorder in which 42% of participants reported chronic pain at baseline, prevalence of chronic pain as well as scores for pain intensity and interference decreased significantly with buprenorphine/naloxone. A past history of heroin use, but not baseline chronic pain, among participants with prescription opioid use disorder was associated with increased opioid use during buprenorphine/naloxone treatment, although higher pain severity at baseline did predict higher buprenorphine/naloxone dose during initial stabilization. The majority of participants with prescription opioid use disorder and chronic pain at study baseline reported that their first source of prescription opioids was a legitimate prescription taken for physical pain. Higher pain severity scores in a given week during buprenorphine/naloxone treatment was significantly associated with opioid use in the subsequent week, with an increase from one pain severity category to the next (e.g., from mild to moderate pain) associated with a 32%–52% increase in the odds of opioid use in the following week. Together these findings suggest that buprenorphine is an effective analgesic with an improved safety profile compared to full opioid agonists in patients with and without opioid use disorder and that worsening pain during buprenorphine/naloxone treatment for opioid use disorder is a risk factor for opioid relapse.

Similar to methadone, patients with opioid use disorder and pain may require different dosing of buprenorphine for treatment of pain versus opioid use disorder. While once-daily buprenorphine dosing is recommended for treating opioid use disorder, improved analgesia may result from splitting the daily dose to three or four times daily. There has been controversy concerning whether buprenorphine's partial agonist “ceiling effect” may limit the analgesia obtained from buprenorphine. Early rodent studies suggested a ceiling effect on analgesia hypothesized to be due to buprenorphine effects at the antinociceptive ORL1 receptor, but clinical studies have failed to demonstrate an analgesic ceiling for buprenorphine in humans. Buprenorphine has a very high affinity for the mu-opioid receptor and a long half-life and as a result doses sufficient to saturate available mu receptors (>16 mg sublingual buprenorphine) will block the euphoric and analgesic effects of other opioids. Of note, patients sometimes misattribute this opioid antagonizing effect of buprenorphine to naloxone in the buprenorphine/naloxone formulation but when taken sublingually naloxone is poorly absorbed. While blocking of opioid agonist effects is an advantage of buprenorphine when treating opioid use disorder, high doses of buprenorphine may also antagonize the analgesic effects of other opioids thereby complicating management of pain in patients maintained on high-dose buprenorphine. Transdermal and buccal buprenorphine formulations approved for treating pain can be used with short-acting opioid full agonists for management of “breakthrough pain” although use of these formulations in patients with opioid use disorder should be done with caution as analgesic doses of buprenorphine may not antagonize euphorigenic opioid effects or deter concomitant use of opioids including heroin.

Management of surgical or procedural analgesia in patients maintained on opioid blocking doses of buprenorphine is complicated. Randomized trials to determine the optimal management strategy are lacking but current consensus is that for minor surgical or diagnostic procedures buprenorphine can be continued and nonopioid analgesics added but there is controversy regarding the best plan for major surgery or procedures expected to result in significant pain. Some experts recommend buprenorphine be discontinued at least 72 h prior to a major surgery/procedure to avoid buprenorphine antagonizing other opioid analgesics followed by close monitoring for potential opioid relapse off buprenorphine and pain management with high affinity full opioid agonists (e.g., fentanyl) and nonopioid modalities. Others recommend continuing buprenorphine and supplementing with high affinity full opioid agonists able to compete with buprenorphine thereby providing additional analgesia while reducing opioid withdrawal and relapse risk related to discontinuing buprenorphine. Although potential antagonism of opioid analgesic effects was not examined, buprenorphine blockade of other opioid agonist effects (subjective, reinforcing, and physiologic effects) is dose dependent and high doses (>24–32 mg sublingually) are required to significantly antagonize other opioids. Controlled clinical trials to identify the optimal strategy for managing surgical/procedural pain in buprenorphine maintained patients are needed, especially in light of newly approved buprenorphine depot formulations which will make discontinuing buprenorphine prior to surgery/procedure impossible in some cases.

Buprenorphine may be less likely to induce opioid-induced hyperalgesia than full opioid agonists including methadone. There was no difference in hyperalgesia between buprenorphine maintained (N = 18) and methadone maintained (N = 18) patients with opioid use disorder, but in the subgroup of patients abstinent from illicit opioids, hyperalgesia was less with buprenorphine than with methadone treatment suggesting that illicit opioid use may have counteracted antihyperalgesic effects of buprenorphine. A small study found reductions in pain severity and interference and improvements in mood among chronic pain patients on more than 100 mg morphine equivalent following transition to buprenorphine although changes in pain tolerance and threshold assessed via Quantitative Sensory Testing were not statistically significant and many of the improvements in pain and mood had regressed by 6 months. A similar small study found significant reductions in pain intensity scores and improvement in quality of life measures among chronic pain patients transferred from high-dose opioids (mean daily morphine equivalent 550 mg) to buprenorphine. In a randomized, double-blind clinical trial, perioperative buprenorphine had lower rates of postoperative hyperalgesia measured by quantitative sensory testing and lower postoperative pain scores compared to morphine in patients receiving remifentanil infusion during general anesthesia for major lung surgery. Buprenorphine is a kappa opioid receptor antagonist and may reduce hyperalgesia by blocking spinal dynorphin, an endogenous nociceptive kappa opioid agonist.

Pain, especially the chronic pain syndrome, involves strong affective and motivational components and depression and anxiety disorders commonly accompany pain conditions. Buprenorphine has antidepressant effects thought to be mediated by kappa opioid antagonism that may be useful in treating the affective and motivational aspects of pain. Low doses of buprenorphine (0.2–2 mg per day sublingual) have shown promise in improving mood and reducing suicidality among opioid naïve patients with treatment-resistant depression although additional randomized, placebo-controlled trials are needed to determine efficacy of buprenorphine for depression. Buprenorphine increased evoked functional MRI responses to noxious heat in limbic/mesolimbic circuits, brain regions important in the affective component of pain processing, among healthy volunteers. High levels of negative affect are associated with lower analgesic effect and increased hyperalgesia during opioid treatment for chronic low back pain. In addition to treating opioid use disorder and providing analgesia in patients with pain and opioid use disorder, buprenorphine may also reduce the affective aspects of pain and depressive symptoms.

Induction of buprenorphine from high doses of prescription opioids and/or long-acting opioids can be challenging. As a partial opioid agonist with a high affinity for the mu-opioid receptor, buprenorphine will displace other mu-opioid agonists thereby precipitating opioid withdrawal. To avoid precipitating withdrawal, other opioids must be discontinued for 12–72 h and at least moderate physical opioid withdrawal symptoms should be present prior to administering the first dose of buprenorphine. Failure to complete buprenorphine induction may occur when inducting from high opioid doses, due to severe opioid withdrawal symptoms, or when inducting from long-acting opioids due to the need to wait 48–72 h or more prior to starting buprenorphine in order to avoid precipitating withdrawal. Several investigators have demonstrated that very low doses of sublingual or transdermal buprenorphine can be started immediately after stopping full agonist opioids without precipitating withdrawal thereby facilitating buprenorphine induction. Additional studies assessing this method as well as other novel buprenorphine induction strategies would be of great clinical utility especially for patients with pain and opioid use disorder.

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