Tolerance with opioids

Alcohol-dependent people with a physical tolerance are relatively tolerant of some other cerebral depressant drugs (hydrocarbon anaesthetics), but of course the synergism with these drugs still occurs. There is no significant acquired cross-tolerance with opioids. 

Multimodal therapy clonidine seems to have a synergistic effect with opioids. This provides for more intense analgesia with the minimization of some of the adverse effects of either class of drugs. There is some cross-tolerance with opioids however, for patients with high opioid tolerance clonidine is an excellent adjimct... 

In the 12-month safety study (N = 805, 2 1 (alvimopan placebo) randomization) 3 at 0.5 mg twice daily was well tolerated and showed evidence of sustained efficacy when taken continuously for 12 months by patients with nonmalignant pain requiring sustained treatment with opioids. However, unexpectedly, there were more reports of myocardial infarctions in patients treated with 3 at 0.5 mg twice daily compared with placebo-treated patients. The majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of 3, including studies in patients undergoing bowel resection surgery who received 3 at 12 mg twice daily for up to 7 days. A causal relationship with 3 has not been established [29]. 

In the chemistry described in Scheme 6.151, Coats and a group of researchers from Johnson and Johnson utilized successive reductive aminations and Suzuki cross-coupling reactions to prepare a 192-member library of tropanylidene benz-amides [295], This series of tropanylidene opioid agonists proved to be extremely tolerant with regard to structural variation while maintaining excellent opioid activity. 

Tolerance. With repeated administration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief Development of tolerance does not involve the peripheral effects, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. 

Use has not been established with opioid-tolerant children younger than 16 years of age. Keep out of the reach of children. 

As the initial opioid for patients who do not have a proven tolerance to opioids, patients should be treated with Avinza initially at a dose of 30 mg once daily (at 24-hour intervals). The dose of Avinza can be adjusted in increments not greater than 30 mg every 4 days. In the event that breakthrough pain occurs, Avinza may be supplemented with a small dose (5% to 15% of the total daily dose of morphine) of a short-acting analgesic. 

If Kadian is chosen, start with 20 mg in those who do not have a proven tolerance to opioids. Increase at a rate up to 20 mg every other day. Individualize dosage. 

Some patients undergoing long-term opioid treatment develop a tolerance with loss of analgesic efficacy. The mechanisms behind this effect are likely to be multi-faceted and partly determined by individual factors. There is widespread and documented experience that the tolerance developed in a particular individual is not developed in parallel for different opioids. Different sources therefore recommend... 

Depending on the compound and the effect measured, the degree of tolerance may be as great as 35-fold. Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects. It is possible to produce respiratory arrest in a nontolerant person with a dose of 60 mg of morphine, whereas in addicts maximally tolerant to opioids as much as 2000 mg of morphine taken over a 2- or 3-hour period may not produce significant respiratory depression. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions (Table 31-3). 

Many nonsteroidal anti-inflammatory drugs of different chemical structures (Fig. 5) have been introduced for the treatment of inflammatory and painful conditions. Many years of clinical experience with these drugs have shown that there is no induction of tolerance or dependence and no respiratory depression as seen with opioids. The major side-effects of these compounds with COX-1 selectivity or balanced COX-1 and COX-2 inhibition are damage to the gastric mucosa, prolongation of bleeding time and renal failure. 

Individuals who have developed tolerance to opioids and who have overdosed on hydromorphone are not likely to develop the serious depression of the respiratory system that occurs in individuals with no such tolerance who have overdosed on hydromorphone. The typical treatment of narcotic overdoses with narcotic... 

Even the most severe acute pain (that lasting hours to days) can usually be well controlled—with significant but tolerable adverse effects—with currently available analgesics, especially the opioids. Chronic pain (lasting weeks to months), however, is not very satisfactorily managed with opioids. It is now known that in chronic pain, presynaptic receptors on sensory nerve terminals in the periphery contribute to increased excitability of sensory nerve endings (peripheral sensitization). 

Opioids are compounds that bind one or more of the many different opioid receptors in the body. Opioids act primarily on the central nervous system. The selectivity of a given opioid for the various opioid receptors determines its characteristic activity. While many opioids are powerful analgesics, opioids often cause physical dependence and have tolerance issues. Sedation and decreased rate of breathing are also side effects associated with opioids. Despite their problems, opioids are generally the drug of choice for treating severe, acute pain. 

Adverse effects Large doses of meperidine cause tremors, muscle twitches, and rarely, convulsions. The drug differs from opioids in that in large doses it dilates the pupil and causes hyperactive reflexes. Severe hypotension can occur when the drug is administered postoperatively. When used with major neuroleptics, depression is greatly enhanced. Administration to patients taking monoamine oxidase inhibitors (see p. 123) can provoke severe reactions such as convulsions and hyperthermia. Meperidine can cause dependence, and can substitute for morphine or heroin in use by addicts. Cross-tolerance with the other opioids occurs. 

Indeed d9-THC is cross-tolerant with k opioid receptor agonists... 

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