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15 Articles in Volume 19, Issue #3
Analgesics of the Future: The Potential of the Endocannabinoid System
Buprenorphine: A Promising Yet Overlooked Tool
Chronic Pain and the Psychological Stages of Grief
Could a Personalized Approach to Therapy End the War on Pain?
Finally, A Systematic Classification of Pain
Hormone Therapy for Chronic Pain
How to Communicate with a Medical Marijuana Dispensary
Letters: Opioid Conversions; Scrambler Therapy for CRPS
MSK Pain: Time for an Enhanced Assessment Model
National Drug Use & Abuse Trends: Prescribed and Illicit
Neuroplasticity and the Potential to Change Pain Response
Should Emergency Naloxone Be in Schools?
Talking to Patients about Medical Cannabis
Utility of Pulsed Radiofrequency Ablation in Xiphodynia
When Opioid Prescriptions Are Denied

Buprenorphine: A Promising Yet Overlooked Tool

A perspective on why partial agonists such as buprenorphine offer an effective alternative to full opioid agonists.
Pages 33-38

Buprenorphine’s History and Availability

Buprenorphine is one of the least understood opioids. It was unveiled in 1971 and became available for clinical use in Great Britain in 1978. In the United States, buprenorphine has been in use since 1980 in liquid form, mostly as part of perioperative management, and then, in 2002, its sublingual form was approved for substitution treatment of opioid dependence.

In terms of administration, since 2001, buprenorphine has been available in most European countries in 35, 52.5, and 70 mcg/h transdermal patches that deliver the dose over 96 hours. A transdermal buprenorphine patch for pain management became available in the US in early 2011 as 5, 10, and 20 mcg/h doses, and according to package inserts, are to be delivered over 7 days (with 7.5 and 15 mcg/h versions entering the market later). The doses available in the US, which are drastically low compared to those available across the European Union (EU), may be best explained by an FDA concern regarding QT interval prolongation that occurred in several patients during US-based clinical trials. In the US, the buprenorphine patch is FDA indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. Due to its unique properties, its mechanism of action is often misunderstood (see Table I).

The FDA-approved dosing of the buprenorphine patch has only added to existing confusion because doses approved for pain are lower while doses approved for opioid dependence are substantially higher.

In addition to those noted above, meptazinol (Meptid) is a partial mu agonist used primarily in obstetrics in the United Kingdom and other European countries. The two latest preparations to enter the market were Buvidal (buprenorphine, CAM2038) in the EU (a prolonged-release injection solution indicated to treat opioid physical dependence in adults and adolescents older than age 16) and Brixadi in the US (a long-acting partial opioid agonist injection formulation in development for the treatment of opioid use disorder, or OUD). Both are available in two preparations: weekly injections at 8, 16, 24, or 32 mg doses and monthly injections at 64, 96, or 128 mg doses. Table II shows further detail.

Dosing Considerations: Absorption, Equivalency, and Binding

The dosing differences of currently available buprenorphine products are based on the preparations’ varying pharmacokinetic properties (see Table III). Dose equivalency between buprenorphine preparations needs to be considered cautiously due to individual differences among patients and poorly predictable factors that may influence blood level and drug action (eg, absorption, distribution, receptor variances). A dose equivalency should be considered a guide and not a rule; buprenorphine products are not interchangeable regarding exact dosage equivalent. Officially, dose equivalency between morphine and buprenorphine is 1:30-50, where morphine is 1 and buprenorphine is 30 to 50 times more potent, but conversion to morphine equivalents is not practical and may be misleading. (See more detail on conversion below or refer to PPM’s free online Opioid Calculator.)

As shown in Table IV, buprenorphine has a higher affinity to opioid receptors than other opioid agonists and antagonists. This means that if it is added to any of them, buprenorphine could dislodge every one of them, causing withdrawal symptoms. At the same time, this higher affinity means that if other opioids are added to buprenorphine, they are unlikely to dislodge it, and thus unlikely to cause withdrawal. In simple terms, a patient who takes morphine or fentanyl, for instance, could develop withdrawal symptoms upon administration of the first dose of buprenorphine. Conversely, adding morphine or fentanyl to the regimen of a patient who already takes buprenorphine continuously is not likely to be problematic. Thus, many patients on buprenorphine maintenance successfully take breakthrough doses of full opioid agonists (eg, morphine, hydrocodone) to provide additional pain control without adverse reactions.

As demonstrated in Table IV, binding affinity is varied. For example, the Ki value of buprenorphine may be in its lower range while fentanyl is in a higher range. In this case, the addition of fentanyl to buprenorphine may be considered safe. However, if the Ki value for buprenorphine is high and fentanyl is low, unpleasant consequences of adding fentanyl to a buprenorphine regimen may occur. Unfortunately, clinical testing to predict Ki values in patients does not currently exist; instead, individual patient responses are elicited through empirical means.

Buprenorphine by itself may be impressively effective for both control of pain and of opioid craving in opioid-dependent individuals; therefore it is indicated in both situations. Overall, according to Minervini, mixtures of kappa and mu opioids may have therapeutic potential for treating pain, particularly when the mixture has a greater ratio of mu to kappa agonist. If adverse effects of each constituent drug are reduced or avoided, then kappa:mu mixtures may be advantageous compared to mu opioids alone.1

Surgical Considerations

As more patients are treated with buprenorphine for physical dependence or for addiction, now termed opioid use disorder (OUD), surgeons and anesthesiologists need to fully understand how to manage perioperative pain in patients who may be on buprenorphine; discontinuation of this medication may not be necessary and may, in fact, cause pain management problems after discharge.

As reported by Benedetti, et al, a double-blind, randomized controlled trial of 21 post-surgical patients found that buprenorphine was able to control pain but at higher doses than typically needed for nociceptive pain.2 To date, however, there is no full consensus on how to best manage patients on buprenorphine maintenance when the need for surgery arises. Stanford University Medical Center released a policy in 2017 based on findings that patients who had discontinued buprenorphine before surgery “consumed significantly greater amounts of opioid in the immediate postoperative period.” Yet, the pain scores for the two groups were not significantly different.3 The University of Kentucky Health Care System echoes this approach, stating, “Given the increased mortality rate immediately after discontinuing buprenorphine-naloxone, we strongly recommend continuing buprenorphine-naloxone preoperatively to ensure overall patient stability and prevent relapse from stopping and restarting the medication."4 The University of Michigan Health System came to a different opinion in 2015 and continues to recommend the discontinuation of buprenorphine-naloxone and transition to short-acting opioids at least five days before surgery “to ensure opioid receptor availability for pain management purposes."5

(Source: 123RF)

The Indiana Polyclinic approach, where the author practices, is to decrease buprenorphine dose by 25% the week before surgery; decrease it another 25% five days before surgery; and restart the full dose in the post-surgical period. For surgeons who may be especially anxious about this medication, the Polyclinic recommends discontinuation of buprenorphine 24 hours before surgery with a restart in the immediate post-surgical period (see also, Table VI). There does seem to be one absolute consensus, however, across the pain community: For pregnant patients on buprenorphine, that treatment should be maintained to prevent withdrawal during delivery.6

Partial Mu Agonist, Kappa Antagonist: What Does It Mean in Practice?

Buprenorphine tightly binds to mu opioid receptors (MOR) but induces them only partially, which allows for pain control while avoiding the potentially devastating inhibitory effects of MOR, including respiratory depression. Buprenorphine also inhibits the kappa receptor – an action directly opposite to full opioid agonists. As shown in Table V, buprenorphine may be responsible for many phenomena induced by mu receptors. At the same time, the medication may antagonize (ie, diminish) the effects of the kappa opioid receptors (KOR). By decreasing hyperalgesia, buprenorphine thus increases analgesia.7

Personality changes, cognitive impairment, and euphoria may be suppressed by buprenorphine, which is less endocrine suppressive and less immunosuppressive than morphine.8 At the same time, inducing KOR has been associated with abuse, dependence, insomnia, agitation, constipation, and orthostatic hypotension.9,10 Buprenorphine specifically has been associated with these adverse effects as well but, reportedly, euphoria is primarily associated with the first several doses and usually attenuates rapidly (see "Observed Side Effects and Recommendations").

Partial agonism may be better understood if one considers that there are many mu opioid receptor subtypes and that not all of them are agonized or antagonized by different opioids equally. This difference leaves room for other opioids to “take up the slack,” so to speak, and bind to the available receptors when such opioids are added to buprenorphine.

Buprenorphine binds to the MOR tighter than naloxone or naltrexone and, as such, it is poorly antagonized by opioid antagonists. This binding presents a challenge in treating a buprenorphine overdose as the patient sometimes responds insufficiently to antidotes.

As shown in Table IV, the range of binding affinity for opioid antagonists varies from patient to patient, which may explain why using opioid antagonists in some overdose cases may work better than in others. Similarly, the addition of a full mu agonist to buprenorphine may cause displacement and withdrawal in some patients. This situation is not common but has been observed in clinical practice.

The Potential Benefits of Buprenorphine

Pain Control

Effective pain control that is frequently achieved with buprenorphine may, in part, be explained by its property of MOR upregulation, as described above.11 Understandably, partial activation of a more potent receptor may be stronger than full activation of a weaker receptor. Also, buprenorphine facilitates mu receptor migration to cell membranes by which the number of available MOR increases12 and, coupled with their activation, adds to better pain suppression. This may further explain why buprenorphine has been shown to alleviate more pain types than fentanyl.13 In clinical practice, the most potent effect of buprenorphine has been observed in the neuropathic arena. A number of randomized controlled trials of buprenorphine efficacy in pain are available.14-17

The half-life of buprenorphine ranges between 20 to 73 hours, depending on the mode of administration, but its elimination half-life is more difficult to estimate reliably. The drug’s pain-relieving properties last on average 6 to 8 hours. Hence, the most-prescribed regimen of buprenorphine in pain management is twice daily to four times daily. At the same time, some patients have sufficient pain control with daily or less frequent sublingual administration. In long-acting formulations, the frequency of administration may be of lesser concern.18-19

As noted, the Benedetti study showed effective post-surgical pain control with buprenorphine.2 As Quaye and Zhang outlined, maintaining buprenorphine perioperatively does not lead to worsened clinical outcomes. Patients may experience adequate pain control from mu opioid agonists while maintained on buprenorphine.20

As reported by Black and Trevethick, the kappa, and not the mu opioid receptor, is involved in the perception of visceral pain. This suggests that specific targeting of kappa opioid receptors may open up new therapeutic opportunities in the treatment of pain associated with disorders of the gastrointestinal tract.21

Mood Stabilization

Mood improvement has been frequently observed in patients with chronic pain taking buprenorphine due to endorphin influences as well as buprenorphine’s serotonergic effect.22-24 Such properties resulted in an attempt by a pharmaceutical company to seek FDA approval for an antidepressant consisting of a combination of buprenorphine and samidorphan (an otherwise not available MOR antagonist). An FDA advisory panel denied the application over study design and safety concerns.25-26

Formulation & Metabolism

Buprenorphine is highly lipophilic and is available in intravenous, sublingual (SL), and transdermal formulations. Intrathecal use has been reported abroad but is not currently approved in the US. Swallowing buprenorphine diminishes its efficacy due to the first bypass, but it is the preferred route for patients who suffer severe nausea and vomiting with SL use (anecdotally). It is excreted minimally unchanged with bile, feces (68%), and urine (27%) and exhibits a long half-life, ranging from 20 to 44 hours.27

Buprenorphine is metabolized by the P-450 3A4 enzyme system primarily in the liver, as well as the UGT 1A1 and 2B7. This metabolism calls upon its interaction with multiple medications competing for those enzymes and the influence of the 3A4 enzyme inducers and inhibitors. Only up to 30% of buprenorphine metabolism is mediated by cytochrome (CYP) 3A4 and new studies indicate that buprenorphine and norbuprenorphine are not predicted to cause clinically important drug interactions with other drugs metabolized by hepatic P450s. Inhibitors or inducers of CYP 3A4 also are not expected to cause significant alteration of buprenorphine metabolism or effects. Transdermal buprenorphine itself is not expected to cause significant alteration of other drugs’ metabolism because of the low plasma concentrations reached after transdermal application.28 This low concentration also may explain why frequent false negative initial urine drug screens occur for patients on transdermal buprenorphine. False negatives may be seen in confirmatory gas chromatography/mass spectrometry testing as well, falling below the threshold of equipment calibration.

Proper Conversion from a Full Opioid Agonist to a Partial Agonist (Buprenorphine)

Conversion from a full opioid agonist is not difficult if done appropriately and may be done at home, but the author has consistently seen better results with in-office buprenorphine startup. The switch from regular opioid to buprenorphine may present a challenge. For instance, a reckless change may precipitate opioid withdrawal and cause the patient to fail the maintenance phase of treatment. Prior best practice called for the initiation of buprenorphine treatment to be conducted in the office. Based on updated evidence, however, induction of buprenorphine in the home setting is now deemed safe and effective.29,30 The key in this process is to avoid switching from high doses of a full opioid agonist and to aggressively treat emerging withdrawal symptoms. Table VI outlines steps for buprenorphine conversion followed at Indiana Polyclinic.

Conclusion

Buprenorphine offers a promising and safe opioid that is still finding its proper place in both pain and addiction (opioid use disorder) treatments. While buprenorphine is a welcome addition to the pain practitioner’s armamentarium, its optimal use requires appropriate training and experience, more research, and more evidence-based treatment protocols.

As with any opioid medication, buprenorphine preparations may be abused, especially if infused intravenously. The presence of buprenorphine in a patient’s body diminishes a likelihood of abuse of full opioid agonists but does not completely prevent it. Prescribing of any opioid medications, including buprenorphine, should be associated with random urinary drug screening, psychology follow-up, and addiction re-assessments. Physical rehabilitation and interventional treatment should also be a part of any ongoing care for a patient with chronic pain.

Last updated on: May 6, 2019
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Buprenorphine With Naloxone for Chronic Pain
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