Morphine-induced respiratory depression

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

Morphine can cause constipation, spasms of the sphincter of Oddi, urinary retention, and pruritus (secondary to histamine release) (see Table 54-4). In head trauma patients who are not ventilated, morphine-induced respiratory depression can increase intracranial pressure and cloud the neurologic examination results. 

Gairola RL, Gupta PK, Pandley K. Antagonists of morphine-induced respiratory depression. A study in postoperative patients. Anaesthesia 1980 35(1) 17-21. 

A patient who was receiving modified-release morphine for mahgnant pain had a respiratory arrest after intrathecal bupivacaine 12.5 mg. She recovered after treatment with naloxone. Another patient who was taking modified-release morphine was given intrathecal morphine 10 mg and bupivacaine 7.5 mg. He had respiratory distress and became comatose. Morphine-induced respiratory depression was not diagnosed and the patient subsequently died. In both cases, respiratory distress and sedation was probably due to opioid action in the absence of the stimulating effect of pain on respiration, due to the intrathecal bupivacaine (198). 

Konieczko KM, Jones JG, Barrowcliffe MP, Jordan C, Altman DG. Antagonism of morphine-induced respiratory depression with nalmefene. Br J Anaesth 1988 61(3) 318-23. 

The membrane separating fetal blood from maternal blood in the intervillous space, the placental barrier, resembles other membranes, in that hpid-soluble substances diffuse readily but water-soluble substances either do not or diffuse poorly. Thus, for instance, morphine-induced respiratory depression and miosis may occur in both the mother and her newborn infant. The children of narcotic-addicted mothers will be bom with an addiction to narcotics. 

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

Buprenorphine is a semi-synthetic derivative of thebaine, one of the opium alkaloids. It is approximately 30 times as potent as morphine. A dose of 0.3 mg intramuscularly has a duration of analgesic action of 6-18 h. Buprenorphine is also effective sublingually. The average bio-availability by this route is about 55%, but absorption is slow and the time to achieve peak plasma concentrations is variable, with a range of 90-360 min. The onset of action is rather slow (5-15 min) after both intramuscular and intravenous administration, possibly due to slow receptor association. Buprenorphine binds to and dissociates from the p receptor very slowly, which may account for its low potential for physical abuse. It also means that buprenorphine-induced respiratory depression is difficult to reverse with naloxone, even with very high doses. Doxapram may in these circumstances be useful. Drowsiness and dizziness are the most common side effects, although they rarely... 

Cerebral circulation is not affected directly by therapeutic doses of morphine. However, opioid-induced respiratory depression and CO2 retention can result in cerebral vasodilation and an increase in cerebrospinal fluid pressure the pressure increase does not occur when PCO2 is maintained at normal levels by artificial ventilation. 

The history of this class of analgesics might have stopped there were it not for the manifold ancillary activities shown by that molecule. Although still one of the most widely used agents for treatment of severe pain, morphine is a drug that must be used with caution. Side effects include respiratory depression, induction of constipation, and sometimes marked sedation. The one property that most severely limits use of this drug is its propensity to induce physical dependence in patients subjected to more than casual exposure. 

Opium and its derivatives have been employed for centuries for the treatment of pain. Morphine was first synthesized in 1805 and has proven to be one of the most effective analgesic agents available [1], Morphine and its analogs are particularly useful because they diminish pain sensation while maintaining consciousness. However, opiates induce severe side-effects including respiratory depression, nausea, bradycardia and constipation and long-term use of opiates can cause addiction [2]. 

Mediates its effects by activating the microopioid receptor it shows equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. 

Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lullmann, Color Atlas of Pharmacology... 

Respiratory depression At the usual adult dose of 10 mg/70 kg, nalbuphine causes respiratory depression approximately equal to that produced by equal doses of morphine. However, nalbuphine exhibits a ceiling effect increases in dosage beyond 30 mg produce no further respiratory depression. Respiratory depression induced by nalbuphine can be reversed by naloxone. Administer nalbuphine with caution at low doses to patients with impaired respiration (eg, from other medication, uremia, bronchial asthma, severe infection, cyanosis, or respiratory obstructions). 

The earliest attempts to develop a non-dependence-inducing morphine derivative resulted in the preparation of heroin (3,6-diacetylmorphine) by acetylation of morphine (Wright, 1874, Dreser, 1898). The potency of heroin was soon recognized. It underwent more investigation than any other product of the time, and was introduced into clinical medicine in 1898. Reports of its reduced respiratory depression and dependence liability were soon shown to be unfounded, but its analgesic effects in animals and man (twice morphine) were confirmed. Pharmacological examination of acyl derivatives of morphine showed that... 

Side-effects Levorphanol has morphine-type side-effects with significant respiratory depression in the high dose range. It induces morphine type addiction and dependence (Coniam, 1991). 

---