**4.3 Medications for opioid use disorder (MOUD) and their potential utility in the patient with co-occurring chronic pain**

There have been many studies confirming the effectiveness and first-line status of MOUD in the treatment of OUD [24, 43]. Interactions between patients with OUD and the medical system, whether in an emergency department, hospital unit, primary care office, or specialty clinic should whenever possibly include prescription of MOUD coupled with timely, logistically feasible follow-up.

### *4.3.1 Buprenorphine*

A semi-synthetic derivative of thebaine developed in the 1980s as an analgesic, buprenorphine is a complex and commonly misunderstood opioid. In the United States, the sublingual formulation was approved by the Food and Drug Administration (FDA) in 2002 for the indication of treatment of opioid dependence (DSM-4 equivalent of opioid use disorder). Its use was limited by restrictions placed on potential prescribers, who were mandated to undergo formal education and training along with application and official authorization by the Drug Enforcement Agency (DEA) to legally prescribe buprenorphine for OUD. These restrictions, which were intended to prevent diversion of the drug, have resulted in a persistently low percentage of available prescribers relative to candidates for use, and a resultant catastrophic unmet need. Further, the implications of these restrictions have led many practitioners to falsely conclude that learning to prescribe buprenorphine is cumbersome, difficult, and better left to others, such as addiction specialists. Tragically, as noted above, at least 80% of individuals with OUD receive no treatment. Ironically, buprenorphine is an extremely safe opioid, indeed safer than not only all other reasonably potent opioids but also many non-opioid medications that all practitioners who treat pain commonly prescribe. Currently, as of the writing of this chapter, there is legislation pending in the US Congress that would remove restrictions on the prescription of buprenorphine for the treatment of OUD.

Buprenorphine's pharmacology includes highly potent mu-opioid receptor (MOR) activity, at least 50 times the analgesic potency of morphine, along with kappa-opioid receptor antagonist activity and delta-opioid receptor agonist activity. Buprenorphine's antagonism at the kappa opioid receptor contributes to an anti-depressant effect, as well as contributing to its ability to diminish and resolve tolerance and hyperalgesia resulting from prolonged use of other opioids. Its delta agonism may contribute to additional analgesia. Its primary metabolite, norbuprenorphine, is unable to cross the blood-brain barrier, which therefore mitigates overdose risk, as brain stem opioid receptors are spared; the opioid receptors in the reward circuitry/limbic system are also spared, which is why buprenorphine can be given to patients with OUD and there is no reinforcing effect. Due to this combination of high potency, excellent safety profile, and lack of psychoactive effect, buprenorphine evolved from its origins as an analgesic to become a first-line treatment for opioid use disorder.

### *Management of Co-Occurring SUD and Chronic Pain DOI: http://dx.doi.org/10.5772/intechopen.105721*

The utility of buprenorphine in the treatment of chronic pain is even more underappreciated and misunderstood. Due to the above-described legal restrictions, the marketing of the sublingual formulation as a treatment for OUD, and knowledge gaps around its pharmacology, many practitioners are unaware of the advantages of buprenorphine as a medication for patients with chronic pain who require or benefit from a long-acting opioid [44]. There are multiple formulations of buprenorphine that can be used effectively as an analgesic, including transdermal buprenorphine, which was approved in 2010; buccal buprenorphine (brand name Belbuca), approved in 2015; and the sublingual formulation, described above and still approved for the treatment of OUD and not pain, even though buprenorphine's analgesic effects are dose-dependent, and the sublingual formulation is the most potent of any of them. One of the common misconceptions around buprenorphine's pharmacology is that there is a "ceiling effect" for analgesia. In fact, the existence of a ceiling effect pertains specifically and exclusively to respiratory depression, but not to analgesia, which is dose-dependent [45].

### *4.3.2 Methadone*

Methadone is an older synthetic opioid analgesic developed in Germany and introduced in the US in 1947 [46]. It was first described in the treatment of opioid (heroin) addiction in 1965 [47]. It has complex pharmacology, particularly with respect to its long and variable half-life (about 24 hours) and pharmacokinetic properties which, combined with its high potency, pose a significant risk of harm when prescribed by providers less well-versed in best practices around its use, or when it is misused. Due to the delicate nature of initiation of methadone and conversion to stable dosing following transition from other opioids, it has been suggested that only health care providers experienced with this process should undergo this task [48].

For treatment of OUD, since its inception in this context, methadone has been federally regulated and required to be dispensed in a licensed opioid treatment program (OTP), rather than in a typical medical office setting. This is one major practical distinguishing feature from buprenorphine. Many OTP facilities provide not only the medication, which is dispensed daily on-site in liquid formulation, but also support services such as counseling, medical care, and complementary treatment such as acupuncture. For these reasons, methadone's utility in current OUD treatment remains strong, particularly for individuals who benefit from the more rigid structure and robust support of the OTP setting.

Methadone poses significant and unique risk factors within the opioid class, however. It exhibits large inter-individual variation in both bioavailability and elimination half-life. Further, there is a major disconnect between its analgesic effect of only about 6–12 hours, contrasted with half-life of up to 59 hours. Patients will sometimes make the dangerous mistake of taking more than instructed as they are trying to get stabilized during initiation. Each dose's respiratory depressant effect can last up to several days and is cumulative over regular dosing, so too high a starting dose, or overuse of the prescribed dose, is particularly problematic during this early phase before the drug has reached a steady state, which normally takes about five days. Methadone is particularly risky for patients co-prescribed or otherwise using benzodiazepines or other CNS depressants, conferring additional overdose risk. Lastly, particularly at higher doses, methadone can prolong the QT interval on an electrocardiogram (ECG) which is a sign of potential cardiac arrest. It is prudent to check a baseline ECG before methadone is initiated. Some have suggested checking again at 50 mg, 100 mg, and any incremental increase of 20 mg thereafter, though there is no clear consensus [48].

Methadone does offer some attractive pharmacologic advantages as a potent long-acting opioid analgesic compared to other options. It is an N-methyl-d-aspartate (NMDA) receptor antagonist as well as a serotonin-norepinephrine reuptake inhibitor, which together may contribute to its anti-hyperalgesic effect after transitioning from other opioids, as well as its reputation for effectiveness in neuropathic pain syndromes [48].

### *4.3.3 Naltrexone*

Developed in the 1970s, naltrexone is a long-acting competitive antagonist at opioid receptors with the capacity to block the subjective and objective effects of opioids [49]. It is an effective antagonist at mu- and kappa-opioid receptors, less so at the delta subtype. It is thought to block glutamate and may contribute to reduction in craving for and protracted withdrawal from alcohol through that mechanism.

Oral naltrexone was approved by the FDA in 1984 for "blockade of the effects of exogenously administered opioids" [49]. It is also approved for alcohol use disorder. Its onset is rapid, reaching peak plasma level within 1 hour, and has a relatively brief half-life of 4 hours. It is metabolized by the liver and severe liver impairment may be an obstacle to use.

An extended-release, injectable formulation of naltrexone was approved in 2006 first for treatment of alcohol use disorder, with opioid use disorder following in 2010. It is administered intramuscularly in the gluteal region, and is typically well-tolerated, particularly with a period of several days of use of oral naltrexone prior to injection [49]. The most common adverse effects are injection site pain, nausea, other gastrointestinal upset, or flu-like symptoms. The formulation contains 380 mg of naltrexone, releasing levels of 1 ng/mL or above for a period of 4–5 weeks, without the need to adjust the dose for weight, age, health status, or other factors.

Studies comparing the effectiveness of ER-naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) for the treatment of opioid use disorder have been performed. In the "X:BOT" study, a multicenter, open-label randomized controlled trial published in 2018 and funded by the National Institutes of Drug Abuse (NIDA) Clinical Trials Network, the 2 medications were found to be equally safe and effective once initiated [50]. Some patients had more difficulty with initiation of XR-NTX compared to BUP-NX, which was in part due to a lack of formal optimization and uniformity of induction and withdrawal protocols between testing sites, of which there were 8 around the country. Authors concluded that the research community should prioritize improving XR-NTX induction and retention strategies. In a more recent study published in JAMA in 2022, however, Xu and colleagues importantly found that buprenorphine outperformed naltrexone in the category of decreasing overdose risk [51].

Naltrexone in compounded oral formulation has been used in the context of chronic pain in the form of "low dose naltrexone" for treatment of CNS-mediated generalized pain syndromes such as fibromyalgia, inflammatory bowel conditions, or multiple sclerosis. Dosing is generally in the range of 4–5 mg daily, whereas daily dose for treatment of OUD is 50 mg. It is thought to work as a modulator of glial cells and inflammatory chemicals in the CNS. It was systematically reviewed in 2020 with favorable findings suggesting a need for further investigation and increased clinical use [52].

Patients may find it difficult to know which of the 3 above-described medications approved for OUD to choose, particularly in the context of chronic pain. Although individual cases will vary, generally it would not be advisable to choose naltrexone for patients with the following circumstances:


Whichever of these evidence-based treatment options is ultimately pursued, it is critical that patients are carefully matched to the best MOUD treatment for their specific circumstances and needs, then monitored and supported to optimize stability in the patient-provider relationship to foster best outcomes.
