Moderate to severe pain
5, 7.5, 10, 15, 20 μg/h
2, 8 mg
Opioid dependence, induction
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, 12 mg/3 mg
Opioid dependence, maintenance
In 2002, the US Federal Drug Administration approved two sublingual buprenorphine preparations for the treatment of opioid abuse. Subutex, a tablet, is approved for opioid maintenance therapy or initial induction during detoxification from illicit opioids. Suboxone is a film of buprenorphine/naloxone in a 4:1 ratio . The drug has also been used off-label as a combination maintenance therapy and analgesic for patients with chronic pain and a history of opioid dependence. Naloxone, a full mu receptor antagonist, has poor sublingual bioavailability. The parenteral bioavailability of naloxone, however, is high. If the tablet is crushed and injected, naloxone induces withdrawal symptoms in opioid-dependent users. The naloxone addition deters misuse of the medication [2, 3]. Buprenorphine/naloxone should not be used for the detoxification phase of opioid replacement therapy because naloxone may precipitate withdrawal.
Buprenorphine and buprenorphine/naloxone formulations used in opioid replacement therapy may be managed in the outpatient setting because of low abuse potential, favorable safety profile, and the long duration of action. The Drug Addiction Treatment Act categorized buprenorphine as a Schedule III drug that can be used on an outpatient basis. Patients are provided a 1-month supply to self-administer the medication (unlike methadone, which typically requires daily witnessed distribution in methadone clinics). Outpatient management of opioid dependence has increased patient access to treatment and mitigates the social stigma frequently associated with methadone maintenance programs. Physicians are licensed to prescribe buprenorphine by completing 8 h of continuing medical education courses on buprenorphine before submitting an application to the Substance Abuse and Mental Health Services Administration. Physicians must also be able to refer patients to counseling and other consulting services and be qualified by the Drug Enforcement Agency to prescribe controlled substances. Once approved, physicians may prescribe buprenorphine/naloxone to 30 patients during the first year, then up to 100 patients after the first year [3, 4, 12]. Table 49.2 summarizes the requirements to prescribe buprenorphine therapy.
Physician requirements to prescribe buprenorphine
• Complete 8 h of continuing medical education courses on the treatment of patients with opioid dependence
• Hold a license under state law
• Register with the Drug Enforcement Administration to dispense opioids
• Treat 30 patients or fewer during the first year of qualification
• Have the resources to refer patients to counseling services
49.3 Perioperative Buprenorphine Management
Evidence-based guidelines for the perioperative management of buprenorphine are not available, but four succinct recommendations exist within the literature. These are based on case reports, expert opinion, and pharmacologic principles.
49.3.1 Continuing Buprenorphine Therapy
In lower-dose regimens, the patient’s daily maintenance dose of buprenorphine may be continued perioperatively, and short-acting full opioid receptor agonists are supplemented to treat acute pain. Because of opioid tolerance and partial mu receptor blockade by buprenorphine, large doses of opioids should be anticipated to compete with buprenorphine at the receptor. Intravenous patient-controlled analgesia (IV-PCA) requirements should be titrated to effect but may be three times higher in these patients than in opioid naïve patients . The effective opioid dose results in adequate analgesia without worrisome opioid-related adverse effects including respiratory depression. The preferred supplemental full opioid agonist should be titratable and have high affinity for the mu receptor to effectively compete with buprenorphine. Fentanyl, hydromorphone, and morphine are candidates; codeine and hydrocodone are not . Fentanyl, highly lipophilic with a rapid onset and short duration of action, is ideal for rapid titration of analgesia without narcosis. Continuing buprenorphine perioperatively prevents buprenorphine withdrawal, and the drug does not need to be resumed after surgery, which can be a complicated process. Case reports document successful perioperative analgesia in patients continued on buprenorphine. In five patients with uninterrupted buprenorphine therapy during general surgical procedures, adequate analgesia was achieved on self-reported or subjective pain scores. All received full mu agonists; two patients also received epidural opioids/bupivacaine, and one received ketamine . In two other cases of obstetric patients on buprenorphine therapy, post-cesarean section pain was adequately managed with an opioid IV-PCA, opioid/local anesthetic epidural solution, and NSAIDs . The disadvantage of continuing buprenorphine perioperatively is the exceptionally high doses of opioids required for adequate pain control. In other case studies, achieving sufficient analgesia was difficult in patients who continued buprenorphine perioperatively, possibly because of partial mu receptor blockade and inability of full agonists to displace buprenorphine from the receptor [7, 17].
The addition of full agonists to provide analgesia for a patient on buprenorphine requires vigilant monitoring of effect. The supplemental dosing of non-titratable agents such as methadone or sustained-release opioids may result in delayed toxicity from gradual displacement of buprenorphine with effector-site concentrations still rising hours after the analgesic threshold is reached. Reducing pain and nociception with non-opioid therapies, such as regional anesthesia and ketamine infusions, may be optimal for continuing buprenorphine perioperatively.
49.3.2 Continuing Buprenorphine with Supplemental Buprenorphine
Buprenorphine can be the sole agent for perioperative pain control because low-dose buprenorphine is predominantly analgesic . The analgesic elimination half-life is 2–6 h. The total daily dose of buprenorphine is divided and administered in equal doses every 6–8 h. In one case of a patient maintained on buprenorphine/naloxone for opioid dependence who also underwent removal of breast implants, pain was adequately controlled postoperatively with her regular maintenance dose and supplemental buprenorphine every 6 h . This method may be useful only for patients with moderate pain who take less than 32 mg buprenorphine daily. There is a ceiling effect on analgesia once doses exceed 32 mg in a 24-h period. Higher doses of buprenorphine are not more analgesic but will block full mu opioid receptor agonists from binding the receptor. This approach prevents exposure to full agonist opioids in patients with a history of opioid abuse. Clinical expertise is needed in buprenorphine supplementation. Patients may take their home buprenorphine if the medication is not on formulary, but any dose increase should be discussed preoperatively and throughout the titration phase with a buprenorphine expert if the primary clinicians do not possess this expertise.