Opioid administration

Opioids are contraindicated in head trauma because of the risk of a rise in intracranial pressure from vasodilation and increased cerebrospinal fluid volume. In addition, in such patients the onset of miosis following opioid administration can mask the pupillary responses used diagnostically for determination of concussion. 

A quantum leap in pain therapy with distinct advantages in the form of reduced side-effects and application frequency was achieved with transdermal opioid administration. Transdermal application requires a number of characteristics on the part of the active substance (Fig. 7), the most restrictive being the daily dose, and only very potent opioids which are effective in very low doses, such as fentanyl and buprenorphine, are an option (Sittl and Likar, 2001). 

Consistent with these hypotheses is the finding that continuous infusion of the opioid into the epidural or intrathecal space provides optimal pain relief postoper-atively or in chronic, intractable pain.2 40 83 Continuous infusion is associated with certain side effects, especially nausea and constipation, as well as the potential for disruption of the drug delivery system.24 57 77 Problems with tolerance have also been reported during continuous administration,27 but it is somewhat controversial whether tolerance really develops when these drugs are used appropriately in the clinical management of pain (see section on Concepts of Addiction, Tolerance, and Physical Dependence ). Hence, the benefit-to-risk ratio for continuous epidural or intrathecal infusion is often acceptable in patients with severe pain. This method of opioid administration continues to gain acceptance.24 57... 

Side effects typically seen when opioids are used for PCA include sedation, pruritus, and gastrointestinal problems (nausea, vomiting). The incidence of these side effects, however, is not significantly increased during PCA versus more traditional methods of opioid administration such as intermittent intramuscular dosing.18 Respiratory depression is another common side effect of opioid use, but again, there is no increased incidence of this problem when appropriate amounts... 

Parkinson, S. K., Bailey, S. L., Little, W. L., and Mueller, J. B. (1990). Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 72, 743—745. 

Morphine or heroin dependence is more disabling physically and socially than is opium dependence (treatment of pain in opioid dependent subjects, see p. 343). Chronic exposure to opioids leads to adaptive changes in the endogenous opioid system and no doubt in receptor numbers, sensitivity and cellular response. The abrupt withdrawal of administered opioid usually provokes rebound or a withdrawal syndrome. This consists largely of the opposite of the normal actions of opioids. Also, noradrenergic mechanisms are modulated by endogenous opioids and these mechanisms are depressed by continuous opioid administration. Abrupt withdrawal reboimd can be described as noradrenergic storm. ... 

Alexander-Williams JM, Rowbotham DJ. Novel routes of opioid administration. Br J Anaesth 1998 81(l) 3-7. 

Musch G, Liposky J. Dysphagia foUowmg intrathecal local anesthetic-opioid administration. J Chn Anesth 1999 11(5) 413-15. 

A strategy for controlling pain caused by malignant disease has been outlined and the classic effects that can be associated with opioid administration have been reviewed (6). These include constipation, nausea, sedation, pruritus, urinary retention, myoclonus, and respiratory depression. The latter can be life-threatening. Particular care is needed in opioid-naive individuals, those with compromised respiratory function, and elderly patients. 

Catatonia is a rare complication of prolonged epidural opioid administration in cancer pain (SEDA-16, 78). Patients with advanced cancer who were taking opioids had significant but transient cognitive impairment when opioid doses were increased (31). This correlates well with studies of the effects of psychotropic medications on ability to drive (32). 

Flushing of the face, neck, and upper thorax can follow therapeutic doses of opioids. These effects may be partly due to release of histamine, which is also implicated in the sweating and pruritus seen after opioid administration. Opioid effects on neurons may partly be involved in the pruritus, as pruritus is provoked by opioids that do not release histamine and is abolished by small doses of naloxone. 

Compared with conventional routes, spinal opioid administration carries potentially greater morbidity and can only be justified if it produces equal or superior pain relief compared with conventional methods, with fewer unwanted effects (SED-11, 139). 

Respiratory depression occurs more often after intrathecal than after epidural opioid administration and can be more of a problem in old age or when there is pre-existing respiratory disease (SED-11, 139) (109,110). The time of onset is variable but usually occurs within 6-10 hours of the opioid injection, although delays of up to 11 hours have been reported (111). There have been two cases of prolonged respiratory depression lasting 18 hours after single doses of 3 and 5 mg (111). Repeated doses of naloxone were required, but each incremental dose did not alter the level of analgesia. 

Respiratory depression occurs less often after epidural than intrathecal opioid administration (109,110). It has been suggested that older patients and those with increased intrathoracic or intra-abdominal pressure are particularly at risk and require reduced dosages (133). In a retrospective study, in which over 6000 patients received epidural morphine, 220 epidural pethidine, and 90 intrathecal morphine, respiratory depression requiring naloxone occurred in about 0.33% after epidural morphine and 5.5% after intrathecal morphine (110). Only two of the patients who received epidural morphine had respiratory depression later than 6 hours after the last dose of opioid. Only three of the 22 patients who had respiratory depression after epidural morphine had not received opioids in addition to epidural morphine during or after the operation. Ten were over 70 years old and 10 had thoracic injections. In another study of 2000 women who received 9000 doses of epidural pethidine 50 mg there was only one case of respiratory depression this was due to migration of the catheter into the subarachnoid space (136). 

Ackerman WE, Juneja MM, Kaczorowski DM, Colclough GW. A comparison of the incidence of pruritus following epidural opioid administration in the parturient. Can J Anaesth 1989 36(4) 388-91. 

Opioids interact specifically with opioid receptors that are present throughout the body but are of primary importance within the CNS. Opioid drugs are used widely in both human and veterinary medicine as adjuncts to anesthesia and post-operatively because of their efficacy as analgesics and their relative safety even in critically ill or compromised patients. However, there are significant species differences in the pharmacological response to opioid administration and their use in the horse has been limited by undesirable physiological and behavioral side-effects and equivocal or short duration of analgesic efficacy (Bennett Steffey 2002). 

Opioids are potent respiratory depressants, causing a dose-dependent decrease in respiratory frequency, tidal volume and minute ventilation and increased arterial partial pressure of carbon dioxide (PaC02) (Carvey 1998). Opioids depress chemosensors in the brainstem, decreasing the ventilatory response to carbon dioxide. Opioids also depress rhythmicity in the dorsal respiratory group in the nucleus tractus solitarius, attenuating the respiratory cycle. Opioids, however, do not diminish hypoxic ventilatory drive. Significant elevations in Paco2 can result in increased ICP after opioid administration. 

TABLE 7—2. Opioid Administration for Acute and Severe Pain... 

With dose escalation of combination oral products, be aware that the dose does not exceed recommended daily amounts for acetaminophen or ibuprofen. IV administration of codeine has been associated with allergic reactions related to histamine release. Parenteral administration of codeine is not recommended. Intermittent opioid administration is associated with wide fluctuation between peak and trough levels so that the patient may alternate between peak blood levels associated with untoward effects and trough levels associated with inadequate pain relief when treating severe pain. 

Ziconotide is neuroprotective in rat models of ischemic neuronal damage and after intrathecal administration, antinociception is observed in rats with limited toxicity. The neuroprotective effects observed in rat models are thought to be due to a reduction in body temperature. Analgesic effects are observed in cancer and AIDS patients whose pain was not relieved after opioid administration and in neuropathic conditions. Intrathecal administration of ziconotide prevents mechanical and cold allodynia and heat hyperalgesia " in neuropathic rats. The use of N-type VSCC inhibitors in both ischemic brain injury and pain treatment is complicated by their important role in the synapse. Adverse effects are observed in patients but they are managed through dose reduction or symptomatic treatment, although serious supraspinal and systemic adverse effects have been seen. ... 

Long-term tolerance may be associated with increases in adenylyl cyclase activity—a counter-regulation to the decreased cyclic AMP levels seen after acute opioid administration. Chronic treatment with p-receptor opioids causes superactivation of adenylyl cyclase. This effect is prevented by pretreatment with pertussis toxin, demonstrating involvement of proteins, and also by cotransfection with scavengers of G protein-py dimers, indicating a role for this complex in superactivation. Recent data, described in the 11th edition of the parent text, argue that opioid tolerance may be related not to receptor desensitization but rather to a lack of desensitization. 

The mechanisms underlying opioid dependence and tolerance are unknown. Chronic administration does not affect opioid receptors, but changes in second messengers may be important, e.g. in the locax coeruteux. p-rccepior activaiion inhibits adenylyl cyclase activity, but with chronic opioid administration the activity of the enzyme increase.s. Withdrawal of the inhibitoty opioid then results in excessive cAMP production, which may contribute to the rebound (incieasc) of neuronal excitability. 

Horlocker TT, Burton AW, Connis RT, Hughes SC, Nickinovich DG, Palmer CM, Pollock JE, Rathmell JP, Rosenquist RW, Swisher JL, Wu CL. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration. Anesthesiology 2009 110(2) 218-30. 

O Brien SH, Fan L, Kelleher KJ. Inpatient use of laxatives during opioid administration in children with sickle cell disease. Pediatr Blood Cancer 2010 54 (4) 559-62. 

Well known as transdermal patches are those containing fentanyl. Fentanyl is used in the treatment of severe chronic pain. Fentanyl is rapidly metabohsed in the hver resulting in low bioavailabihty after oral administration. After apphcation of the patch, 90 % of the released amount reaches the systemic circulation. After first apphcation the plasma concentration increases gradually, stabDises after 12-24 h and is stable up to 72 h [14]. Fentanyl transdermal patches often offer an adequate alternative to parenteral opioid administration in patients who are not able to take their medications orally. 

Pasternak and Pan 2013 Runguphan et al. 2012). These synthesized compounds include hydiocodone, oxycodone, hydromorphone, and oxymorphone. Millions of patients are treated with opioid analgesics (Alexander et al. 2014). Patients requiring chronic opioid administration often have complex medical conditions, and they do not all respond in the same manner, leading to unpredictable individual differences in effectiveness and adverse drug reactions. 

The other three types of tolerance (pharmacokinetic, pharmacodynamic, and learned) are clubbed as acquired tolerance. In contrast to innate tolerance, this type of tolerance develops with continued opioid administration, and thus represents true tolerance rather than genetically mediated lack of sensitivity to opioids. 

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