{
  "abstract": "Opioid therapy for moderate or severe pain due to active cancer relies on pure mu agonist opioid drugs, such as morphine, oxycodone, and fentanyl. Treatment is challenging due to the prevalence and complexity of adverse effects, including those related to abuse or addiction. Buprenorphine and methadone are both mu agonist opioids that are indicated in many countries for the management of pain and opioid use disorder. They have unique properties and may be able to offer better outcomes in specific patient groups or situations.Buprenorphine’s pharmacology involves interactions with all four opioid receptors and other mechanisms. It is a ‘biased agonist’ at the mu receptor, activating different G-proteins with varying effects. It is a delta receptor antagonist, a kappa receptor inverse agonist, and a nociception receptor partial agonist. Its mu receptor interactions are characterized by 1) low intrinsic efficacy (‘partial agonist’), varying across effects; 2) high receptor affinity and slow receptor dissociation; 3) high potency; 4) low recruitment of the beta-arrestin pathway; and 5) varied involvement of spinal vs. brain receptors. It is highly protein-bound and metabolized by the hepatic enzyme CYP3A4 to an active metabolite, norbuprenorphine. Excretion is mostly in the bile. The characteristics of the drug related to these mechanisms underscore its uniqueness: 1) It is efficacious for pain and for the treatment of opioid use disorder; 2) it is associated with a low risk of abuse; 3) there is a ceiling effect for respiratory depression but not for pain; 4) during therapy, concomitant use of a short acting pure mu agonist, like morphine, will produce analgesic effects; 5) given its binding profile, it can displace other opioids from the receptor and produce so-called precipitated withdrawal; 6) the binding affinity also means that naloxone will work for buprenorphine overdose only if given in high doses for prolonged periods; 7) it does not cause hypogonadism or opioid dysimmune effects; 8) it does not prolong the QTc interval; 9) drug-drug interactions occur with inhibitors or inducers of CYP3A4; and 10) typically, no dose adjustment is needed in the setting of renal or hepatic impairment. In sum, buprenorphine is efficacious and has a better safety profile than pure mu agonist drugs. If clinicians have access to the drug at an acceptable cost, treatment should be considered if there is an ongoing risk of drug abuse or addiction, there is significant or declining renal function, or the patient has may benefit from a drug with a lower risk of adverse effects, including hypoventiliation and hypogonadism. To safely switch from relatively high dose opioid therapy to buprenorphine, clinicians should be aware of the risk of precipitated withdrawal and use an accepted approach to minimize the likelihood.Methadone is a pure mu agonist and an agonist at the delta and kappa receptors; its effects are related to these interactions and to two other mechanisms—antagonism of presynaptic neuronal NMDA receptors, which are believed to be involved in the development of hyperalgesia and opioid tolerance, and activity in serotonin and norepinephrine pathways that may be active in pain modulation. Methadone is hepatically-metabolized, mostly by CYP3A4, and is also mostly excreted in bile. It is notable for its high degree of pharmacokinetic and pharmacodynamic inter-individual variation. For example, oral bioavailability varies from 36% to 100% and half-life varies from 4 hours to 190 hours. Drug-drug interactions are common and pharmacodynamic variation is very large when switching from another opioid to methadone. In the latter scenario, the relative potency ratio that is used to calculate an equianalgesic dose can vary 100-fold across patients; the drug to use when switching to methadone becomes particularly hard to predict when the dose of the prior drug is relatively high. The characteristics of methadone related to these mechanisms reveal its uniqueness: 1) It is low-cost and efficacious for pain; 2) observational studies suggest that efficacy and potency can be unpredictably high when the drug is used as a second-line agent following one or more unsuccessful trials of opioid therapy for pain; 3) the large inter-individual variation in half-life and other pharmacokinetic parameters impart a risk of unintentional overdose whenever methadone is used; 4) it is an effective treatment for opioid use disorder and has a low risk of abuse; 5) it can prolong the QTc interval; 6) drug-drug interactions occur with inhibitors or inducers of CYP3A4; and 7) typically, no dose adjustment is needed in the setting of renal or hepatic impairment. In sum, methadone is efficacious, has a poorer overall safety profile than other pure mu agonist drugs, but may be useful if administered by knowledgeable clinicians to mitigate the risk of abuse or addiction, undertake an opioid trial after other trials have proved unsuccessful, or switch to a lower cost therapy. To safely switch from relatively high dose opioid therapy to methadone, clinicians should be aware of the risk of unintentional overdose and use an accepted approach to minimize the risk.Both methadone and buprenorphine have the potential to improve opioid outcomes in selected patients with cancer pain. To address the needs of patients with cancer pain, clinicians should acquire the knowledge and skills necessary to use these drugs safely and effectively.",
  "authors": [
    {
      "affiliations": [
        "Albert Einstein College of Medicine, USA"
      ],
      "name": "Russell Portenoy"
    }
  ],
  "title": "S1-4 Buprenorphine and methadone in the treatment of cancer pain",
  "uid": "fc6b95bf-b086-5615-854a-7dc661ffe2c3"
}