Mixed Opioid Agonist–Antagonists or Partial Agonists

Mixed Opioid Agonist–Antagonists or Partial Agonists

The mixed opioid agonist–antagonists are potent anal-gesics in opioid-naive patients but precipitate with-drawal in patients who are physically dependent on opi-oids. They are useful for the treatment of mild to moderate pain. They were developed to reduce the ad-diction potential of the opioids while retaining the anal-gesic potency of the drugs. Their analgesic effect is gen-erally attributed to an interaction at the κ- and to a lesser extent the μ-opioid receptor.

Interaction at the μ-receptor increases the sedative effects of the drugs. The euphoric effects are due to in-teraction with the κ-receptor. The dysphoric and psy-chotomimetic side effects of the drugs are attributed to interaction at the σ-receptor.

The mixed agonist–antagonists and partial agonists differ from morphine in that they (1) produce excita-tory and hallucinogenic effects, (2) produce a low de-gree of physical dependence, (3) induce withdrawal signs that differ from those of morphine, and (4) pro-duce excitatory effects related to the sympathetic dis-charge of norepinephrine and therefore are positive in-otropic agents in the heart.

Pentazocine

Pharmacological Effects

Pentazocine (Talwin) is a potent analgesic with an-tagonistic activity in opioid-addicted patients. It incom-pletely blocks the effects of morphine in such patients but will precipitate withdrawal. To eliminate abuse of the drug via IV administration, pentazocine is com-bined with naloxone (Talwin-NX). IV administration of Talwin-NX will produce no analgesic or euphoric ef-fects because naloxone blocks the pentazocine moiety. However, the drug will retain its analgesic potency when administered orally, since naloxone is not active orally. Pentazocine produces as much respiratory de-pression as morphine but does not produce the same degree of constipation or the biliary constriction ob-served with morphine. Pentazocine may increase GI motility if used in high doses. Unlike morphine, penta-zocine increases heart rate and blood pressure by re-leasing norepinephrine. Pentazocine also may increase uterine contractions in pregnancy.

Pharmacokinetics

Absorption of pentazocine following oral administra-tion is rapid. The onset of action occurs within approxi-mately 15 minutes, and the half-life is 2 to 3 hours. Pentazocine is extensively metabolized in the liver and thus has a high first-pass effect following oral administra-tion; its half-life differs considerably from patient to pa-tient. Oxidation of the methyl groups followed by conju-gation to glucuronides in the liver terminates the effects of pentazocine. Excretion occurs through the kidney.

Clinical Uses

Pentazocine is indicated for relief of moderate pain in patients not receiving large doses of opioids. It is also used as premedication for anesthesia and as a supple-ment to surgical anesthesia.

Adverse Effects

The most common side effect of pentazocine is se-dation resulting from an interaction with the κ-receptor. Also observed are sweating, dizziness, psychotomimetic effects, anxiety, nightmares, and headache. Nausea and vomiting are less frequent than with morphine. Respiratory depression and increased heart rate, body temperature, and blood pressure accompany overdose. Naloxone is effective in reducing the respiratory de-pression but requires the use of higher doses than for morphine overdose.

Contraindications

Most of the contraindications specific to penta-zocine stem from its excitatory effects. Other con-traindications are similar to those for morphine. Pentazocine is contraindicated in patients with myo-cardial infarction because it increases heart rate and cardiac load. Similarly, it is contraindicated in epileptic patients because it decreases seizure threshold. In addi-tion, in head trauma patients, it can increase intracranial pressure and brain injury. Pentazocine use in patients with psychoses is contraindicated because of its psy-chotomimetic side effects.

Drug Interactions

The combination of pentazocine with the antihista-mine tripelennamine results in a combination known to drug abusers as T’s and blues. This combination pro-duces heroinlike subjective effects, and heroin addicts use it in the absence of heroin. In addition, the use of pentazocine in combination with alcohol or barbitu-rates greatly enhances its sedative and respiratory de-pressant effects.

Tolerance and Dependence

Tolerance to the analgesic effects of pentazocine de-velops. Withdrawal signs are milder than those seen with morphine, and they produce more excitatory effects.

Butorphanol

Butorphanol (Stadol) is chemically related to levor-phanol but pharmacologically similar in action to pen-tazocine. As an opioid antagonist it is nearly 30 times as potent as pentazocine and has one-fortieth the potency of naloxone. It is a potent opioid analgesic indicated for the relief of moderate to severe pain. Its potency is 7 times that of morphine and 20 times that of pentazocine as an analgesic. Its onset of action is similar to that of morphine. The side effects and signs of toxicity are sim-ilar to those produced by pentazocine. It produces exci-tatory effects and sedation and precipitates withdrawal in opioid-dependent patients. Although generally ad-ministered parenterally because of its low bioavailabil-ity following oral administration, it is also unique in that a nasal spray formulation is available. The nasal spray is indicated for the relief of postoperative pain and mi-graine headache. The low molecular weight of butor-phanol, its high lipophilicity, and its lack of vasocon-strictor effects make it particularly suitable for nasal administration.

Nasal administration of butorphanol decreases the onset of action to 15 minutes and decreases the first-pass effect of the drug, which increases bioavailability. Generally the patient sprays a set dose of 1 mg per hour for 2 hours. The duration of action is 4 to 5 hours. The convenience of such administration is a major advantage to patients requiring repeat dosing. The abuse potential following such administration has not been extensively studied, although it is thought to be small. Butorphanol is not a federally controlled (“scheduled”) drug, so physicians are not required to obtain the licenses and security safeguards required for other opioid analgesics.

Adverse effects, contraindications, and drug interac-tions are similar to those for pentazocine and morphine.

Nalbuphine

Nalbuphine (Nubain) is a mixed agonist–antagonist that is similar in structure to both the antagonist naloxone and the agonist oxymorphone. It is administered par-enterally and is equipotent to morphine and 5 times as potent as pentazocine. Although the pharmacological ef-fects (analgesia, respiratory depression, sedation, and so on) are similar to those produced by pentazocine, nal-buphine produces fewer psychotomimetic effects. It dif-fers from pentazocine in that it has far greater antagonist than agonist effect. Thus, its use is likely to precipitate se-vere withdrawal in opioid-dependent patients. It is used much as pentazocine is, that is, for moderate to severe pain, postsurgical anesthesia, and obstetrical analgesia. Nalbuphine’s abuse potential is less than that of codeine and propoxyphene, although tolerance and dependence have been shown following chronic administration. High doses are perceived by addicts as being like those of the barbiturates. Drug interactions and contraindications are similar to those for pentazocine and morphine.

Buprenorphine

Buprenorphine (Temgesic) is a mixed agonist–antago-nist and a derivative of the naturally occurring opioid thebaine. Buprenorphine is highly lipophilic and is 25 to 50 times more potent than morphine as an analgesic. The sedation and respiratory depression it causes are more intense and longer lasting than those produced by morphine. Its respiratory depressant effects are not readily reversed by naloxone. It binds to the μ-receptor with high affinity and only slowly dissociates from the receptor, which may explain the lack of naloxone rever-sal of respiratory depression.

Buprenorphine has more agonist than antagonist ef-fects and is often considered a partial agonist rather than a mixed agonist–antagonist, although it precipi-tates withdrawal in opioid-dependent patients. Its phar-macological effects are similar to those produced by both morphine and pentazocine. Indications for its use are similar to those of pentazocine, that is, for moderate to severe pain. Sublingual preparations are available, but have a slow onset and erratic absorption.

The abuse potential of buprenorphine is low. While high doses of the drug are perceived by addicts as being morphinelike, it does reduce the craving for morphine and for the stimulant cocaine. Thus, buprenorphine is a potential new therapy for the treatment of addiction to both classes of drugs.

Drug interactions and contraindications are similar to those described for pentazocine and morphine.

Dezocine

Dezocine (Dalgan) is a synthetic aminotetralin deriva-tive with potent agonist–antagonist effects. The onset of activity and potency as an analgesic are comparable to those of morphine. Although the drug requires glu-curonidation during metabolism, patients with hepatic insufficiency clear it normally. The main route for clear-ance is the kidney. Thus, patients with renal dysfunction are prone to buildup of dezocine over time. As an an-tagonist, dezocine is more potent than pentazocine. As an agonist, dezocine produces analgesia and respiratory depression (which is readily reversed by naloxone), but unlike pentazocine, it has little if any effect on the car-diovascular system.

Dezocine is indicated as an analgesic for moderate to severe pain. In addition, it shows promise in chronic pain states, such as with victims of severe burns. Contraindications and adverse effects of the drug are similar to those described for morphine. No tendency toward abuse has been demonstrated thus far.