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Coadministration of an Opioid Agonist and Antagonist for Pain Control

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Coadministration of an Opioid Agonist and Antagonist for Pain Control REVIEW ARTICLE Coadministration of an Opioid Agonist and Antagonist for Pain Control Dima Rozen, MD::·; Carson Ling, MD*; Cris Schade, MD, PhD fJppt *Department of Anesthesia and Pain Management, Mount Sinai Hospital, New York, NY U.S.A.; tPrivate Practice, Garland, TX • Abstract: The increased use of opioids in the treatment heterogeneous group of drugs with moderate ro strong of chronic pain encourages the search for drugs with low analgesic activity but with a limited effective dose range. abuse and tolerance potential but with potent analgesic The group includes drugs that act as agonists or partial activity. Opioid agonist-antagonists and partial agonists have agonists at one receptor and as antagonists at another.• less abuse potential than do mu opioid receptor agonists such as morphine, and have been used for many years for There are three major classes of opioid receptor sites their analgesic affects. Recently they have been approved for involved in analgesia: mu, delta, and kappa. Most clin­ treatment of opioid addiction. As a guard against abuse, an ically useful opioid analgesics bind to mu-opioid recep­ opioid antagonist, such as naloxone, is added to some opioid tor sites and are the mainstay for controlling acute and formulations. Doctors are often hesitant to prescribe agonist­ cancer pain. Examples include morphine, codeine, antagonists and partial agonists to opioid-tolerant patients, fentanyl, hydrocodone, hydromorphone, merperidine, fearing that these drugs may precipitate withdrawal. Can methadone, oxycodone, and propoxyphene.2 Pentazo­ drugs being used safely for addiction treatment also safely cine and butorphanol are partial mu-agonists and replace opioid agonists to provide analgesia in chronic pain patients who are opioid-tolerant? • kappa-agonists. Nalbuphine is a mu-antagonist and kappa-agonist. Buprenorphine is a partial mu-agonist 3 4 Key Words: agonist-antagonist, pentazocine, buprenor­ and kappa-antagonist. • It is recommended that mu phine, chronic pain, opioid, addiction, mu receptor, kappa receptor partial agonists and antagonists be avoided (or receptor, opioid withdrawal, naloxone used with caution) in patients receiving mu-agonist opi­ oids, as they can reverse opioid effects and precipitate PREMISE withdrawal syndrome. It is common for partial agonises and mixed agonises­ Drugs in the mixed agonists-antagonisrs-partial antagonists to be discussed as a group. The agonist­ antagonist group of interest for sustained treatment of antagonist and partial agonist opioid analgesics are a chronic pain are those available for oral including sub­ lingual, use. Formulations that include pentazocine and Address correspondence and reprint requests to: Dima Rozen, MD, buprenorphine fir this criterion. Buprenorphine formu­ Assistant Professor of Anesthesiology, Director of Neuromodulation, lations show considerable potential for use in chronic Department of Anesthesia and Pain Management, Mount Sinai Hospital, pain treatment. 5 East 98th Street, 6th Floor, New York, NY 10029-6574, U.S.A. Tel: 212· 241-6471; Fax: 212·384-8695; E-mail: dimarozenCHotmaii.com. PENTAZOCINE <0 2005 World lriS/llute of Pam, 1530-70851051$!5.00 TALWIN N:x-1 contains pentazocine hydrochloride, USP, J'ai11 Practtee, Volume 5, lss11e 1, 2005 11 -17 equivalent to 50 mg base and naloxone hydrochloride, 12 • ROZEN ET AL. USP, equivalent to 0.5 mg base. It is formulated for oral BUPRENORPHINE administration. Pentazocine has the following structural Suboxone (CHI) is a sublingual tablet that contains formula: buprenorphine HCI and naloxone HCI dihydrate at a H ratio of 4 to 1, buprenorphine, naloxone (ratio of free bases). Subutex is a sublingual tablet that contains buprenorphine HCI. Suboxone is available as sublingual tablets containing 2 mg of buprenorphine with 0.5 mg of naloxone and 8 mg of buprenorphine with 2 mg of HO naloxone. Subutex is available as 2 mg and 8 mg of I buprenorphine sublingual tablets. Buprenorphine has CH 3 the following structure: It is a potent analgesic which when administered HO orally in a 50 mg dose appears equivalent in analgesic effect to 60 mg (1 grain) of codeine. Onset of signifi­ cant analgesia usually occurs between 15 and 30 minutes after oral administration, and duration of .HCI action is usually 3 hours or longer. Onset and duration of action and the degree of pain relief are related both to dose and the severity of pretreatment pain. Pentazo­ cine weakly antagonizes the analgesic effects of mor­ Molecular weight: 504.09 phine and meperidine; in addition, it produces Buprenorphine 0.3 mg i.m. is approximately equiva­ incomplete reversal of cardiovascular, respiratory, and lent co 10 mg morphine sulfate i.m. in analgesic and behavioral depression induced by morphine and mepe­ respiratory depressant effects in adults. Pharmacological ridine. Pentazocine has about 1/50 the antagonistic effects occur as soon as 15 minutes after intramuscular activity of nalorphine. It also has sedative activity. The injection and persist for 6 hours or longer. Peak phar­ presence of naloxone in TALWIN Nx will prevent the macologic effects usually are observed at 1 hour.6 effect of pentazocine if the product is misused by injec­ Although buprenorphine may be classified as a partial tion. Studies in animals indicate that naloxone does not agonist, under the conditions of recommended use it affect pentazocine analgesia when the combination is behaves very much like a classical mu agonist. One given orally. If the combination is given by injection, unusual property of buprenorphine observed in in vitro the action of pentazocine is neutralized. TALWIN Nx is studies is its very slow rate of dissociation from its indicated for the relief of moderate to severe pain. receptor. This could account for its longer duration of Some patients previously given opioids, including action than morphine, the unpredictability of its reversal methadone, for the daily treatment of opioid depen­ by opioid antagonists, and its low level of manifest dence, have experienced withdrawal symptoms after physical dependence. Buprenorphine demonstrates opi­ receiving pentazocine. Patients receiving therapeutic oid antagonist activity and has been shown to be equi­ doses of pentazocine have experienced hallucinations potent with naloxone as an antagonist of morphine in (usually visual), disorientation, and confusion, which the mouse tail flick test. Buprenorphine is indicated for have cleared spontaneously within a period of hours. the relief of moderate to severe pain. The mechanism of this reaction is not known. There have been some reports of dependence and of with­ drawal symptoms with orally administered pentazo­ Treating Chronic Pain cine. The usual initial adult dose is 1 to 2 tablets every The mixed agonist-antagonist analgesics have not had 3 or 4 hours. Total daily dosage should not exceed 12 a major role in the treatment of chronic pain, but the tablets. Tolerance to the analgesic effect of pentazocine use of Suboxone is gaining popularity. Pentazocine, the has also been reported only rarely. However, there are first and most widely used of this group of drugs has no peer-reviewed reports on the long-term experience two major limitations: by mouth it is not a strong anal­ with the oral admmistration of TALWIN Nx, but anec­ gesic and its use is associated with psychotomimetic side dotally no adverse effects have been observed by the effects in 10 to 20 percent of patients.7 Buprenorphine authors from long-term use. is the most useful of the agonist-antagonists in chronic Coadministration of an Opioid Agonist and Antagonist • 13 pain patients. It is potent, long-acting (6 to 9 hours) and abuse histories. Compared to typical [mu ]-agonist opi­ effective when given sublingually. However, it has a oids, buprenorphine appears to produce less physical limited effective dose range (analgesic ceiling at 32 mg dependence, 10 abuse liability,4 and respiratory depres­ sublingual per day) and produces the same side effects sion.• • In addition, buprenorphine blocks the euphoric as morphine-like drugs, possibly more frequently at effects of [mu]-agonist12 and has a longer duration of equianalgesic doses. It may be used in the treatment of analgesia (6 to 8 hours), thus requiring infrequent self­ cancer pain, or in patients with chronic arthritides or adminisrration.11 The main problem in switching ro other forms of chronic noncancer pain who require a buprenorphine therapy for the treatment of pain is potent conventional analgesic, as an alternative to the that it can precipitate withdrawal from fmu)-agonist weak opioids or to morphine in low doses.x Suboxone opioids.13 has an additional prescribing advantage because it has As a mu opioid partial agonist, buprenorphine may the analgesic potency of the class II controlled sub­ act as a mu agonist or antagonist depending on the stances bur it is scheduled as a class III controlled sub­ pharmacological test, the degree of receptor activation 14 11 stance. The Drug Enforcement Administration (DEA) required to produce agonist effects, • and the dos­ "X" license is nor required when it is prescribed as a age. When buprenorphine, with its high affinity for pain medication. The Drug Addiction Treatment Act of the mu receptor, displaces a full agonist with greater 2000 expanded treatment for opioid dependence into intrinsic activity from that mu receptor, the activation mainstream medical practice. It specifies several ways in produced by buprenorphine is less. Buprenorphine has which physicians can qualify ro prescribe and dispense low intrinsic activity (and high affinity) at the mu 3 4 buprenorphine in their offices for the treatment of opi­ receptor. • That is, it binds tightly to this receptor, but otd dependence. A practitioner who wants to use it does not "turn on" this receptor as completely as a buprenorphine for substance abuse treatment must full mu-opioid agonist. Conversely, buprenorphine has apply for a wavier and meet all of the requirements no intrinsic activity (but high affinity) at kappa recep­ under 21 U.S.C. § 823(g)(2)(B). The DEA will then tors.
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