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.
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.
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.
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.
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