Opioid analgesic
Opioid analgesics, also called narcotics, are drugs usually used for treating pain. Opioid analgesics are defined as "all of the natural and semisynthetic alkaloid derivatives from opium, their pharmacologically similar synthetic surrogates, as well as all other compounds whose opioid-like actions are blocked by the nonselective opioid receptor antagonist naloxone.[1]
Pharmacology
There a several opioid receptors. All are are G-protein-coupled cell surface receptors. Clinically useful analgesic families vary in their receptor effects; they range from pure agonists of all receptor types, to selective agonists, to agonist-antagonists.
| Receptor | Functions |
|---|---|
| Delta | Analgesia, |
| Kappa | Analgesia, inhibition of gastrointestinal motility, psychotropic effect |
| Mu | Analgesia, inhibition of gastrointestinal motility, inhibition of respiration, sedation and physical dependency |
Available opioid analgesics
Current opioid analgesics are below [3]
Tables of morphine equivalent daily dose and IV to PO conversion are available to help dosing, although direct conversion is unwise with opioids with complex pharmacodynamics, such as methadone.
A number of oral forms are combined with acetaminophen to reduce the possibility of diversion to injected abuse, although acetaminophen also has a distinct and potentially synergistic analgesic effect. Acetaminophen has been found to be more toxic, with or without opioids, than had been generally believed, and the FDA has recommended restrictions on its uses.Cite error: Closing </ref> missing for <ref> tag
The American Pain Foundation is concerned that these recommendations consider the matter carefully, lest there be undertreatment with appropriate opioids. [4] Combination with aspirin and other non-narcotic agents was common before the widespread use of acetaminophen
| Specific drug | Potency relative to morphine[5]0 | Chemical class | Receptor action | Metabolism[6][7] | Comments |
|---|---|---|---|---|---|
| Naturally occurring opium alkaloids | |||||
| Morphine | 1 | morphine | mu, kappa (weak) | ||
| Codeine | 0.15 | morphine | mu (partial agonist) | Good oral absorption | |
| Semi-synthetic opioids | |||||
| Diacetylmorphine (heroin) | morphine | Faster blood-brain transfer than morphine but both produce the same primary active metabolite | |||
| Hydrocodone and Oxycodone | 1 1.5 |
morphine | mu (partial) | ||
| Hydromorphone (Dilaudid) | 4 | morphine | mu | Mostly hepatic | Oral bioavailability is approximately 24%[8] |
| Buprenorphine | Thebaine | mu, antagonist of delta and kappa | |||
| Fully synthetic opioids | |||||
| Meperidine | 0.1 | Meperidine | mu | Good oral absorption; toxic metabolite accumulates on prolonged use | |
| Fentanyl | 2.4 | Meperidine | mu | Transdermal and transmucosal absorption | |
| Methadone | 3 | methadone | mu | Good oral absorption. Bioavailability of methadone ranges between 36 to 100%.[9] Different half-lives for analgesia and for blocking withdrawal | |
| Tramadol | 0.1 | codeine | mu | Also inhibits monoamine oxidase; can raise norepinephrine and serotonin, and cause serotonin syndrome | |
| Propoxyphene | 0.23 | propoxyphene | mu | L-isomer is antitussive; analgesic D-isomer was removed from the U.S. market as too risky for its limited effectiveness.Cite error: Closing </ref> missing for <ref> tag In emergency rooms, non-Hispanic white patients are more likely to receive narcotics than patients of other ethnicities.[10]
Opioids are effective for both short (1-16 weeks)[11]. Opioids may[12][13] or may not (in patients with lumbago)[14] be effective for long-term (6-24 months). In a randomized controlled trial with active placebo, morphine for nine weeks reduced chronic pain but not improve functional status.[15] AdministrationClinical practice guidelines are available.[16] Tables of morphine equivalent daily dose and IV to PO conversion are available to help dosing, but must be used with caution. Some opioids, such as methadone, do not lend themselves to simple conversion due to greatly differing half-lives. While an antagonist or partial antagonist may have equianalgesic dosing in an opioid-naive patient, switching from, for example, long-term morphine to buprenorphine can cause withdrawal. Routes of administrationMost opioids can be administered parenterally. Recent developments have provided alternate formulation that improve oral effectiveness of drugs historically injected, such as morphine. Novel routes are being found effective, such as transdermal skin patches that provide a constant low-rate dose, and transmucosal and intranasal routes for quick action. Chronic useFear of addiction had long interfered with the extended use of opioids even in terminal patients. Current practice, however, includes the indefinite use of opioids in nonterminal patients with pain that can only be controlled by opioids. The World Health Organization, for example, has a "pain pyramid" for rheumatic disease, which begins with acetaminophen or equivalents, and moves to increasingly powerful opioids. Long-term opioid therapy is prescribed both for analgesia, and also the treatment of opioid dependence. Mortality may be increased upon both starting and topic opioid maintenance.[17] Appropriate use may be improved with prescription-drug monitoring programs in which prescribers can track all opioid prescriptions for a patient. This has been studied for the Ohio Automated Rx Reporting System (OARRS).[18] Two additional systems under development are bu the United States Department of Health and Human Services and one by the Department of Justice.[19] Opioid treatment agreements and urine drug testing may reduce opioid misuse by patients with chronic pain. [20] Advice for using administering chronic narcotics[16] and for treating acute pain among patients on chronic methadone is available[21]. Special technique may also be needed for patients receiving buprenorphine for chronic pain. There are challenges in prescribing opioids with specialized actions, such as partial agonists and mixed agonist/antagonists. These may interfere with the effectiveness of breakthrough medications for additional acute pain. Such drugs also may be ineffective or produce withdrawal in patients receiving other long-term opioids. Adverse effectsNarcotics, with long-term use, 80% of patients may have drug toxicity, most commonly gastrointestinal. In addition, substance abuse and "aberrant medication-taking behaviors" may occur.[14] Serious drug toxicity from long-term use may be low according to one systematic review.[13] ConstipationConstipation may be reduced by methylnaltrexone, a mu-opioid receptor antagonist. In a randomized controlled trial, 48% of patients receiving methylnaltrexone had a bowel movement compared to 15% of patients received placebo (number needed to treat = 3.0. Click here to adjust these results for patients at higher or lower risk.)[22] Although mu-receptors provide analgesia, methylnaltrexone is a charged quaternary amine so that it does not well cross the blood-brain barrier. Dietary agents and inert physical agents may help. A high-fiber diet is desirable, possibly with fiber supplements such as psyllium and metacellulose. The stool softener docusate is often prescribed. Stronger laxatives are not desirable. Male hypogonadismChronic opioids may cause male hypogonadism.[23][24] Impaired judgmentOpioids may increase risk of traffic accidents.[25] DependencyOpioid agonist therapy includes buprenorphine and methadone. Although buprenorphine–naloxone may be less effective than methadone[26], it has more predictable dosing[27], and can be prescribed by qualifying office-based physicians.[28] OverdoseChronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.[29] This may be more common with long acting opioids.[30] Nevertheless, when the dose is managed by experts, the dose of most opioids can be raised indefinitely when needed to relieve pain. [31] In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.[32] Substance abuseWith chronic use for treatment of pain, dependency may lead to substance abuse and "aberrant medication-taking behaviors" may occur.[14] From 2000-2005, the abuse of prescribed opiods, especially oxycodone extended release (OxyContin) and hydrocodone, has increased.[33] From Contracts may reduce abuse, but comparative studies provide conflicting results.[34] Most agreements stated, "patients agreed not to abuse illicit drugs or alcohol, obtain opioids from more than 1 provider or pharmacy, or request a refill before the previous prescription should have been completed." WithdrawalAdding narcotic antagonists combined with alpha-adrenergic agonists may reduce withdrawal symptoms.[35] ToleranceN-methyl-d-aspartate receptor (NMDA) activation may lead to neuropathic pain and tolerance.[36][37] Methadone, which is a NMDA antagonist, may reduce tolerance. PruritisPruritis from histamine release may occur.[38] Anecdotally, one of the reason for using antihistamines as adjuvants, such as hydroxyzine and promethazine, are to alleviate some of these side effects, as well as nausea. The less sedating hydroxyzine also may potentiate analgesia and have a better antipruritic effect although promethazine may be stronger against nausea. References
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