Respiratory depression opioid analgesics

It is worth mentioning that iV-allylic substitution in a number of morphine derivatives, as a rule, leads to antagonistic properties. Naloxone is a few times stronger than nalorphine as an antagonist. It blocks opiate receptors. It eliminates central and peripheral action of opioids, including respiratory depression. Naloxone is used upon overdose of narcotic analgesics.Synonyms for this drug are narkan, talwin, and others. 

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. 

However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Research is ongoing to understand and develop analgesic agents and adjuncts that avoid this effect. Research to overcome this problem is focused on 5 receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers. 

This situation became particularly acute with respect to the development of illicit analogs of fentanyl to derive heroin substitutes. Fentanyl is a synthetic opioid, a p-receptor agonist, and is about 100-200 times more potent than morphine as an analgesic. As with other narcotic analgesics, respiratory depression is the most significant acute toxic effect of the fentanyl derivatives. Fentanyl analogs can be 80-1000... 

The most serious side effect of the opioids is respiratory depression.The narcotic agonists suppress the brainstem respiratory centers and thus alter tidal volume, respiratory rate, rhythmicity, and responsiveness to CO2. When used in equianalgesic doses, the opioids, with the exception of pentazocine, produce similar degrees of respiratory depression.Therapeutic doses of opioid analgesics are unlikely to produce significant respiratory depression in most healthy patients.The opioids must be used with caution, however, in patients with preexisting pulmonary disease, especially patients with airway compromise such as chronic obstructive pulmonary disease. 

Dextromethorphan HBr is the ( + )-isomer of the 3-methoxy form of the synthetic opioid levorphanol. It lacks the analgesic, respiratory depressant, and abuse potential of p opioid agonists but retains the centrally acting antitussive action. Dextromethorphan is not an opioid and is not listed in the Controlled Substances Act. Its effectiveness as an antitussive is less than that of codeine. Dextromethorphan is available in a number of nonprescription cough formulations. 

Risk of opioid-induced respiratory depression, nausea, vomiting, and constipation. Risk of monoamine excitabihty and possible serotonin syndrome. Tapentadol should not be used during breast feeding. Like other extended-duration opioids, the cost of tapentadol ER will probably be higher than immediate-release opioid analgesics. 

Angst MS, Chu LF, Tingle MS, Shafer SL, Clark JD, Drover DR. No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans. Pain 2009 142(1) 17-26. 

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. 

They act as analgesics by inhibiting release of nociceptive neurotransmitters from primary afferent terminals as well as by depressing post-synaptic potentials on second order neurons. Opioid receptors are also present on some nociceptors and their expression and peripheral transport is increased upon peripheral inflammation. Peripheral opioid analgesia has been established in animal models. Although clinical studies have yielded mixed results so far, this field holds great promise. Despite side effects, such as euphoria, dysphoria, sedation, respiratory depression and obstipation and tolerance and dependence phenomena which arise upon... 

Epidural analgesia is frequently used for lower extremity procedures and pain (e.g., knee surgery, labor pain, and some abdominal procedures). Intermittent bolus or continuous infusion of preservative-free opioids (morphine, hydromorphone, or fentanyl) and local anesthetics (bupivacaine) may be used for epidural analgesia. Opiates given by this route may cause pruritus that is relieved by naloxone. Adverse effects including respiratory depression, hypotension, and urinary retention may occur. When epidural routes are used in narcotic-dependent patients, systemic analgesics must also be used to prevent withdrawal since the opioid is not absorbed and remains in the epidural space. Doses of opioids used in epidural analgesia are 10 times less than intravenous doses, and intrathecal doses are 10 times less than epidural doses (i.e., 10 mg of IV morphine is equivalent to 1 mg epidural morphine and 0.1 mg of intrathecally administered morphine).45... 

This class produces analgesia and has a ceiling effect on respiratory depression and lower abuse potential than morphine. However, psychotomimetic responses (e.g., hallucinations and dysphoria with pentazocine), a ceiling analgesic effect, and the propensity to initiate withdrawal in opioid-dependent patients have limited their widespread use. 

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

These differences in the behavioural properties of the opioid receptor sub-types are of considerable interest because the clinical use of currently marketed opioid analgesic drugs is limited by their undesirable side-effects, which include respiratory depression, constipation and an abuse or dependence liability. These side-effects have been associated with mu receptor ac-... 

Morphine and other opioids work by activating a family of opioid receptors in the brain. These fall into three classes and morphine activates all of them. It has proved possible to design and synthesize opioids that are more-or-less specihc for snbsets of the opioid receptors. However, none of these has proved to have the right set of activities to retain the potent analgesic power of morphine withont the addiction potential and respiratory depression potential. Finding such a molecule remains on ongoing challenge. 

Tramadol is an opioid analgesic, which acts by exerting an opioid effect and through the stimulation of adrenergic and serotonin pathways. Compared with the other opioids, tramadol is less likely to cause the typical opioid side-effects, such as respiratory depression, and constipation. It is also less likely to cause addiction. 

Oxycodone CR tablets are not intended for use as an as-needed analgesic. Oxycodone 80 and 160 mg CR tablets are for use in opioid-tolerant patients only. These tablet strengths may cause fatal respiratory depression when administered to patients not previously exposed to opioids. 

Concomitant narcotic administration - The respiratory depressant effect of fentanyl may persist longer than the analgesic effect. Consider the total dose of all opioid analgesics used before ordering narcotic analgesics during recovery from anesthesia. Use opioids in reduced doses initially, %to 1/3 those usually recommended. 

Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists, such as naloxone. Because the duration of respiratory depression may last longer than the duration of the opioid antagonist action, maintain appropriate surveillance. 

A series of peptides, occurring naturally in brain and possessing pharmacological properties similar to those of morphine, have been described. At least three separate families of peptides have opioid properties (Table 24.2), and the different classes of peptides reside in separate distinct neurons. It is likely that the endogenous opioid peptides coexist in neurons with other nonopioid neurotransmitters. The initial hope that these endogenous agents or synthetic derivatives of them would be found to retain the analgesic activity of the opioids but be devoid of respiratory depression and/or addictive properties has now somewhat abated. 

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