Complex Action Opioids and Opioid Antagonists

COMPLEX ACTION OPIOIDS AND OPIOID ANTAGONISTS

1. Agonist-antagonists (κ analgesics)

Nalorphine, Pentazocine, Butorphanol

2. Partial/weak µ agonist + κ  antagonist

Buprenorphine

3. Pure antagonists

Naloxone, Naltrexone, Nalmefene

Clinically, the agonist-antagonist (agonist at one opioid receptor, antagonist at another) and partial/weak agonist (low intrinsic activity) opioids are analgesics of comparable efficacy to low doses of morphine, but with a limited dose range. They cause low ceiling respiratory depression and have lower abuse potential. However, in only few situations they have proven to be advantageous over the full μ receptor agonists.

Nalorphine

It is N-allyl-normorphine; was the first opioid antagonist introduced in 1951 which could reverse morphine action. Later it was found to have agonistic actions as well. Nalorphine is a κ agonist and μ antagonist; has analgesic action with a lower ceiling, but is not used clinically because of dysphoric and psychotomimetic effects. Naloxone has replaced it as a morphine antidote.

Pentazocine 

It is the first agonist-antagonist to be used as an analgesic. It has weak antagonistic and more marked κ agonistic actions. The profile of action is similar to morphine; important differences are:

·      Analgesia caused by pentazocine is primarily spinal (κ₁) and has a different character than that caused by morphine. Parenterally 30 mg pentazocine = 10 mg morphine; but ceiling effect is lower, i.e. at higher doses proportionate increase in analgesia does not occur.

·      Sedation and respiratory depression is 1/3 to 1/2 of morphine at lower doses, and has a lower ceiling, does not increase much beyond 60 mg dose.

·   Tachycardia and rise in BP are produced due to sympathetic stimulation. This may increase cardiac work; better avoided in coronary ischaemia and myocardial infarction.

·      Biliary spasm and constipation are less severe.

·      Vomiting is less frequent. Other side effects are sweating and light-headedness.

·  Subjective effects are pleasurable (morphinelike) at lower doses: recognised by postaddicts as an opiate. However, as dose is increased, these become unpleasant (nalorphinelike at > 60 mg i.m.) and psychotomimetic effects (κ, σ mediated) appear.

Tolerance, psychological and physical dependence to pentazocine develops on repeated use. Withdrawal syndrome has features of both morphine and nalorphine abstinence, but is milder in intensity. ‘Drug seeking’ occurs. Abuse liability is rated lower than morphine.

Injected in morphine dependent subjects, it precipitates withdrawal. Antagonistic action is 1/5th as potent as nalorphine: not enough to be useful in morphine poisoning. In pentazocine dependent subjects, high dose of naloxone precipitates withdrawal.

Pharmacokinetics And Use Pentazocine is effective orally, though considerable first pass metabolism occurs; oral: parenteral ratio is 1 : 3. It is oxidized and glucuronide conjugated in liver and excreted in urine. Plasma t½ is 3–4 hours, duration of action of a single dose is 4–6 hours.

Oral  dose:  50–100 mg, efficacy like codeine.

Parenteral dose: 30–60 mg i.m., s.c., may cause local fibrosis on repeated injection due to irritant property. FORTWIN 25 mg tab., 30 mg/ml inj., PENTAWIN, SUSEVIN 30 mg/ml inj.

Pentazocine is indicated for postoperative and moderately severe pain in burns, trauma, fracture, cancer, etc. Though abuse liability is low, frequent side effects and potential for dysphoric/psychotomimetic effect limits its utility in chronic (cancer) pain.

Butorphanol

It is a κ analgesic, similar to but more potent than pentazocine (butorphanol 2 mg = pentazocine 30 mg). Likewise, analgesia and respiratory depression have a lower ceiling than morphine. Sedation, nausea, cardiac stimulation and other side effects are similar to pentazocine, but subjective effects are less dysphoric. Psychotomimetic effects are less marked (it is a weaker σ agonist at higher doses). BP is not increased.

Post-addicts recognize it as a barbiturate rather than opiate and mostly dislike it. However, it produces physical dependence; withdrawal can be precipitated by high dose of naloxone, but the syndrome is mild. The abuse potential of butorphanol is low. The most outstanding feature is that butorphanol can neither substitute for nor antagonize morphine. This shows its very weak interaction with μ receptors.

It has been used in a dose of 1–4 mg i.m. or i.v. for postoperative and other shortlasting (e.g. renal colic) painful conditions, but should be avoided in patients with cardiac ischaemia. The duration of action is similar to morphine.

BUTRUM 1 mg/ml, 2 mg/ml inj.

Buprenorphine

It is a synthetic thebaine congener, highly lipid-soluble μ analgesic that is 25 times more potent than morphine. It has a slower onset and longer duration of action. After a single dose, analgesia lasts for 6–8 hours; but with repeated use, duration of action increases to ~24 hours. Certain other effects last still longer.

Sedation, vomiting, miosis, subjective and cardiovascular effects are similar to morphine, but constipation is less marked. Postural hypotension is prominent. Respiratory depression (and analgesia) exhibit ceiling effect. It substitutes for morphine at low levels of dependence but precipitates withdrawal in highly dependent subjects, reflecting its partial agonistic action at μ receptors. Antagonistic action on κ receptor has also been described.

Lower degree of tolerance and physical as well as psychological dependence develops with buprenorphine on chronic use. Its withdrawal syndrome resembles that of morphine, but is delayed for several days, is milder and longer lasting. ‘Drug seeking’ is present. Abuse liability is rated lower than morphine.

Even naloxone (at high dose) only partially reverses buprenorphine effects and does not precipitate its withdrawal; probably because of more tight binding of buprenorphine to opioid receptors.

Buprenorphine has good efficacy by sublingual route, is highly plasma protein bound and remains in tissues for several days; t½ is 40 hours. It is mostly excreted unchanged in bile and finds its way out of the body in faeces.

Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual 0.2–0.4 mg 6–8 hourly.

NORPHIN, TIDIGESIC 0.3 mg/ml inj. 1 and 2 ml amps. 0.2 mg sublingual tab; BUPRIGESIC, PENTOREL 0.3

mg/ml inj in 1, 2 ml amp.

Use:

Buprenorphine is indicated for long-lasting painful conditions requiring an opioid analgesic, e.g. cancer pain. It has also been recommended for premedication, postoperative pain, in myocardial infarction and in the treatment of morphine dependence.

Buprenorphine is not suitable for use during labour, because if respiratory depression occurs in the neonate, it cannot be effectively reversed by naloxone.

Nalbuphine, Meptazinol and Dezocine are other agonist-antagonist opioids introduced in some countries.