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Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain

Last updated: 06-05-2020

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Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain

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Despite proven clinical utility, buprenorphine has not been used widely for the treatment of chronic pain. Questions about “ceiling effect” or bell-shaped curve observed for analgesia in preclinical studies and potential withdrawal issues on combining with marketed μ-agonists continue to hinder progress in expanding full potential of buprenorphine in the treatment of cancer and noncancer pain. Mounting evidence from clinical studies and conclusions drawn by a panel of experts strongly support superior safety and efficacy profile of buprenorphine vs marketed opioids. No ceiling on analgesic effect has been reported in clinical studies. The receptor pharmacology and pharmacokinetics profile of buprenorphine is complex but unique and contributes to its distinct safety and efficacy. The buprenorphine pharmacology also allows it to be combined with other μ-receptor opioids for additivity in efficacy. Transdermal delivery products of buprenorphine have been preferred choices for the management of pain but new delivery options are under investigation for the treatment of both opioid dependence and chronic pain.

Opioids are the market leaders for treatment of moderate to severe chronic pain among adults, amounting to over $10 billion in global sales. The opioids are emerging as the primary option for cancer pain treatment as approximately 70% of cancer patients and 85% of those suffering from cancer-related pain eventually require management with opioids.1,2 The use of opioids is also increasing for treatment of chronic nonmalignant pain with established benefits in inflammatory, ischemic, visceral, musculoskeletal, and neuropathic pain.3,4 Despite rising opioid prescriptions (11.8% in 2010 in US), many patients feel nonsatisfactory response to treatment options.5 In addition, long-term use of opioid therapy leads to the development of tolerance and hyperalgesia limiting their clinical utility in controlling chronic pain. Chronic use of opioids also accounts for other side effects such as respiratory depression, constipation, dependence, and abuse potential. With a growing senior population (projected to be approximately 25% by 2020 in major markets), there is constant demand for more efficacious and safer treatment options for patients.

Buprenorphine () is a semi synthetic derivative of an opiate alkaloid thebaine that is isolated from the poppy Papaver somniferum. Buprenorphine is a hydrophobic molecule and carries a complex chemical structure with multiple chiral centers. Buprenorphine was introduced in the early 1980s as an opioid analgesic in Europe and subsequently for the treatment of opioid addiction in France in 1996. It is available in the US for the treatment of opioid addiction maintenance programs, and for the treatment of chronic pain.

Buprenorphine has a distinct profile, significantly different from morphine, codeine, fentanyl, or methadone. It is a potent but partial agonist of μ-opioid receptor (μ-OR), showing a high affinity but low intrinsic activity (). High potency and slow off rate (half-life of association/dissociation is 2–5 hours)6 help buprenorphine displace other μ-agonists such as morphine, methadone from receptors and overcome opioid dependence issues. Buprenorphine is approximately 25–100 times more potent than morphine. The slow dissociation from μ-receptor also accounts for its prolonged therapeutic effect to treat opioid dependence as well as pain.

The in vitro profile of buprenorphine against ORs is captured in .7 The clinical relevance of interactions of buprenorphine with different ORs is not fully resolved but the knowledge on its unique profile is improving with emerging data. Buprenorphine is a potent κ-receptor antagonist (Ki =6 nM) and this is believed to resist depression.8,9 Buprenorphine acts as a “chaperone” ligand and increases μ-receptor expression on membrane surfaces.2,10,11,12 Buprenorphine is also an agonist for nociceptin or OR-like 1 (ORL1) that has a unique interaction with pain processing. Activation of the ORL1 receptor in the dorsal horn is analgesic, but cerebral ORL1 activation blunts antinociception as seen in animal models.12 It has been suggested that μ-receptor mediated antinociception can be reduced by the ORL1 agonist activity residing in the same molecule.13,14 The relevance of ORL1 activation by buprenorphine under clinical setting is, however, not clear particularly at pharmacological doses to control pain. Additional mechanisms have also been proposed for the analgesic effects of buprenorphine. In interesting studies, peripheral administration of naloxone antagonizes buprenorphine’s dose response curve while supraspinal intracerebroventricular (icv) administration of naloxone shows no effect against subcutaneous (sc) administration of buprenorphine in antinociceptive tests. Similarly, icv buprenorphine produces antinociception and intraperitoneal buprenorphine is antagonized by intraperitoneal naloxone, but not by icv naloxone in rat formalin test.15 These results suggest a different supraspinal mechanism of action for buprenorphine. Pertussis toxin which prevents ligand-induced activation of G-protein-coupled receptors (GPCRs), antagonizes morphine, and fentanyl but has no effect on buprenorphine mediated analgesia. Further mechanistic studies suggest the involvement of heterotrimeric guanine nucleotide-binding regulatory protein Gz. Supraspinal administration of Gz antisense had no effect on morphine or fentanyl antinociception but blocked buprenorphine effect. The icv administration of okadaic acid (a protein phosphatase inhibitor) blocked buprenorphine but not morphine or fentanyl effect. Thus, supraspinal component of buprenorphine-induced antinociception does not appear to be mediated via the typical μ-opioid response but by other unique receptors.15

Buprenorphine is a lipophilic molecule (LogP=4.98) with low aqueous solubility. The compound shows high volume of distribution and distributes well in tissues including brain. The protein binding for buprenorphine in human plasma is approximately 96%, not to the albumin but to the α- and β-globulin fractions. Buprenorphine has very low plasma concentrations and this is not believed to influence competition between globulin binding sites.10 Buprenorphine is extensively metabolized in the liver, and the major metabolite norbuprenorphine () occurs through Cyp3A4 mediated N-dealkylation.16,17 Both buprenorphine and norbuprenorphine undergo rapid glucuronidation at the phenolic site by UGT2B7 and UGT1A1 in the liver.16,18 The plasma levels of conjugate metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide can exceed the parent drug levels. In human, norbuprenorphine rarely exceeds 10% of buprenorphine blood concentrations (Cmax).19

The relative bioavailability of buprenorphine given intramuscular (im), sublingual solution or sublingual tablet is 70%, 49%, and 29%, respectively, assuming 100% for intravenous (iv) dosing.20–23 Sublingual and transdermal formulations tend to show long half-life (20–73 hours). The prolonged terminal half-life of buprenorphine can in part be due to enterohepatic recirculation as observed for nonhuman species. With a sublingual formulation, buprenorphine shows onset of effects at 30–60 minutes postdosing and the peak clinical effects are observed at 1–4 hours. The duration of effect may last for 6–12 hours at low dose (16 mg). The longer effect at higher buprenorphine sublingual dose may be linked to sustained, effective drug levels for extended duration because of its slower elimination and enterohepatic recirculation (see for approved doses of sublingual buprenorphine).

Buprenorphine is eliminated primarily via a stool (as free forms of buprenorphine and norbuprenorphine) while 10%–30% of the dose is excreted in urine as conjugated forms of buprenorphine and norbuprenorphine. Buprenorphine is a preferred opioid for treatment of pain in patients with compromised renal function. Buprenorphine is also safer in patients with a failing liver.24

Buprenorphine and its Cyp3A4 mediated metabolite norbuprenorphine are rapidly converted to conjugate. Buprenorphine and norbuprenorphine do not inhibit Cyps at therapeutic doses, and as a result have fewer drug interactions.25 Drugs that inhibit Cyp3A4 do not seem to influence the pharmacokinetics (PK) profile of buprenorphine significantly and glucuronidation is generally associated with limited drug interactions.12 However, caution should be used when buprenorphine is co-administered with other drugs that inhibit Cyp3A4. The combination of buprenorphine with benzodiazepine or other central nervous system (CNS) depressants should be administered with caution as it may lead to severe or even fatal respiratory depression.26

The reported Ki values for ORs for buprenorphine and metabolites vary significantly based on the experimental conditions and the laboratories conducting experiments.7,18,27 Buprenorphine-3-glucuronide is a μ-, δ-, and ORL1 agonist, whereas norbuprenorphine-3-glucuronide is a κ- and ORL1 ligand. All metabolites except norbuprenorphine-3-glucuronide are analgesic and contribute to the observed buprenorphine profile in clinic.18,28 Neither buprenorphine nor the glucuronide metabolites reduce respiratory rates, although norbuprenorphine-3-glucuronide has been demonstrated to reduce tidal volume in animal models.18,29 Norbuprenorphine is a potent μ-agonist and contributes to respiratory depression.30

The primary side effects of buprenorphine are similar to other μ-opioid agonists (eg, nausea, vomiting, and constipation), but the intensity of these side effects is reduced significantly compared to full agonist. The superiority of buprenorphine over other opioids in safety was recently addressed.12

Buprenorphine has a ceiling effect on respiratory depression and remains one of the safest opioids to curtail this adverse effect as concluded by a panel of experts reviewing opioid pharmacology.10,12,31–33 Typically, 1%–11% of patients on opioid therapy suffer from respiratory depression that seems to be more pronounced in seniors, obese, or individuals with sleep apnea or neuromuscular disease. Respiratory depression associated with buprenorphine may be partly related to its metabolite, norbuprenorphine, and not to the parent drug. Interestingly, buprenorphine prevents and reverses respiratory depression in rats that are given lethal injections of norbuprenorphine.34 In another study, much higher safety window (13.5-fold) is reported for buprenorphine than for fentanyl (1.2-fold) when comparing analgesia and respiratory distress doses in rat.35 The combination of buprenorphine with sedative drugs such as benzodiazepine or alcohol has been reported to affect respiratory depression adversely. Buprenorphine–benzodiazepine combination, however, seems safer than methadone–benzodiazepine for respiratory distress.26 Caution should, however, be exercised in combination therapy of buprenorphine with CNS depressants.

Opioid use can impair cognitive function and driving ability. Addiction to opioids can influence dependability. The addition of alcohol or sedatives may worsen the cognitive and driving ability. Comparative studies done report that buprenorphine may have better visual, psychomotor or cognitive function vs morphine, methadone or fentanyl.12,39 In many cases, buprenorphine effect on cognitive and psychomotor function was comparable to placebo.40

Opioids seem to trigger unique biochemical communication between brain and the immune system. The reported data suggest that while exogenous opioids suppress the immune system, the endogenous opioids stimulate it. The implications of opioid evoked immunosuppression are particularly relevant during the postoperative period when the pain and susceptibility to infection are high; for sufferers of chronic pain who administer opioids for extended periods; and for patients with immunosuppressive disease such as AIDS, transplant patients, and the elderly, who are predisposed to opportunistic infections.41 The potent opioids such as morphine and fentanyl reduce antibody production, reduce natural killer cell activity, and impair the cytokine expression and phagocytic activity of white cells.12 The immunosuppressive effect is accentuated in presence of corticosteroids or other immunosuppressive drugs. Some immunosuppression in morphine may also emerge through non-μ-receptor mediation as the effect is not reversed by naltrexone.42,43 Unlike morphine, buprenorphine does not reduce natural killer-cell function, increase cortisol, reduce adrenocorticotropic hormone levels, or alter norepinephrine or serotonin levels after injection in the brain. Most of the studies showing lack of immunosuppressive effect of buprenorphine have been conducted in animals and their clinical relevance needs to be established. However, in immunosuppressed patients, opioids (morphine, fentanyl) treatment may be avoided and buprenorphine should be considered in the scheme of options.10,12,43–45

Chronic use of μ-receptor agonists has been associated with hypogonadism and fatigue. With time, hypogonadism can lead to osteopenia and loss of muscle mass. Use of morphine and fentanyl is reported to reduce testosterone levels and testosterone replacement therapy is often recommended. Even at high doses, buprenorphine seems to have minimal effect on sexual hormone levels.46–49

Based on reported data, methadone-maintenance treatment has been associated with QTc prolongation (approximately 29% patients) with approximately 5% showing QTc interval of


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