Opioid analgesic

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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 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.

Metabolism

Some opioids are metabolized by cytochrome P-450 and cytochrome P-450 CYP2D6.[2] [3][4]

Reduced metabolizers of codeine, tramadol, oxycodone, hydrocodone may have reduced effect due to decreased conversion to morphine.[2]

Ultrarapid metabolizers of codeine[5], oxycodone, and hydrocodone may have increased drug toxicity due to increased conversion to morphine.[2]

Available opioid analgesics

Current opioid analgesics are below [6]

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.[7][6] The American Pain Foundation is concerned that these recommendations consider the matter carefully, lest there be undertreatment with appropriate opioids. [8] Combination with aspirin and other non-narcotic agents was common before the widespread use of acetaminophen

Selected opioids[9]
Specific drug Potency relative to oral morphine[10] Chemical class Receptor action Metabolism[11][12] Comments
Naturally occurring opium alkaloids
Morphine 1 morphine mu, kappa (weak)
Codeine 0.15 codeine mu (partial agonist) Good oral absorption
Semi-synthetic opioids
Diacetylmorphine (heroin) 1 morphine mu, kappa (weak) Faster blood-brain transfer than morphine but both produce the same primary active metabolite (morphine prodrug)
Hydrocodone 1 thebaine/codeine mu (partial)
Oxycodone 1.5 thebaine/codeine mu (partial) Oxycodone may increase mortality relative to codeine and hydrocodone[13] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[13]
Hydromorphone (Dilaudid) 4 thebaine mu Mostly hepatic Oral bioavailability is approximately 24%[14]
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
Remifentanil Meperidine mu
Methadone 3 methadone mu Good oral absorption. Bioavailability of methadone ranges between 36 to 100%.[15] Different half-lives for analgesia and for blocking withdrawal
Tramadol 0.1 tramadol 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.[16]

Effectiveness

Opioids are commonly prescribed for pain, and their usage may be increasing.[17] In emergency rooms, non-Hispanic white patients are more likely to receive narcotics than patients of other ethnicities.[17]

Opioids are effective for short term use (1-16 weeks)[18].

Chronic benign pain

For chronic, non-cancer pain, opioids may give short term reduction in pain compared to placebo.[19][20][21]

The role of long term treatment of chronic non-cancer pain is not clear.

One systematic review found that trials of short term opioids did not improve functional status compared to placebo in chronic pain.[19] However, a second systematic review, found that opioids improved functional status compared to placebo, but not compared to other drugs.[21]

As example randomized controlled trials, opioids reduced pain in the short term, but did not improve function in comparison to an cholinergic antagonist placebo[24] or tricyclic antidepressant.[25]

Most trials are funded by industry.[21]

Administration

Clinical practice guidelines are available.[26]

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 administration

Most 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 use

Fear 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.[27]

Advice for using administering chronic narcotics[26] and for treating acute pain among patients on chronic methadone is available[28]. 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.

Monitoring chronic use

Appropriate use may be improved with prescription-drug monitoring programs in which prescribers can track all opioid prescriptions for a patient. In the United States of America, the U.S. Department of Justice's Drug Enforcement Administration coordinates the State Prescription Drug Monitoring Programs. Prescription-drug monitoring programs have been studied for the Ohio Automated Rx Reporting System (OARRS).[29] Two additional systems under development are bu the United States Department of Health and Human Services and one by the Department of Justice.[30]

Opioid treatment agreements and urine drug testing may reduce opioid misuse by patients with chronic pain. [31] Urine drug testing is of two types:[32]

Adverse effects

Opioid analgesics may cause more drug toxicity, at least in geriatrics, than non-selective inhibitors of cyclooxygenase (non-steroidal anti-inflammatory agents) or cyclooxygenase 2 inhibitors.[33]

Oxycodone and codeine may increase mortality relative to codeine and hydrocodone[13] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[13] In contrast to hydrocodone, oxycodone and codeine and metabolized by cytochrome P-450 CYP2D6 which may lead to variable pharmacokinetics due to single-nucleotide polymorphisms and drug interactions.[34]

Opioid analgesics, 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.[20]

Serious drug toxicity from long-term use may be low according to one systematic review.[22]

Constipation

Constipation may be reduced by methylnaltrexone, a mu-opioid receptor antagonist. In a randomized controlled trial of patients with advanced illness, 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.)[35] Although mu-receptors provide analgesia, methylnaltrexone is a charged quaternary amine so that it does not well cross the blood-brain barrier. Methylnaltrexone can also help patients taking chronic opiates for non-malingnant pain.[36]

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 hypogonadism

Chronic opioids may cause male hypogonadism.[37][38]

Employability

Use of opioids may be a risk factor for failing to return to work.[39][40]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.[41]

Impaired judgment

Opioids may increase risk of traffic accidents[42] and accidental falls[43].

Dependency

For more information, see: Opiate dependence.

Opioid agonist therapy includes buprenorphine and methadone. Although buprenorphinenaloxone may be less effective than methadone[44], it has more predictable dosing[45], and can be prescribed by qualifying office-based physicians.[46]

Mortality and Overdose

Number of Poisoning Deaths Involving Opioid Analgesics and Other Drugs or Substances --- United States, 1999--2007.

Death from overdose on opioids may be more common than traffic accidents in the United States.[47] The rate of overdose is increasing faster among women and men according to the Centers for Disease Controll.[48]

Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.[49]

Overdose may be more common with with doses equivalent to more than 100 mg/day of morphine.[50] Overdose may[51] or may not[50] be increased with long acting opioids.

In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.[52]

Substance abuse

With chronic use for treatment of pain, dependency may lead to substance abuse and "aberrant medication-taking behaviors" may occur.[20] From 2000-2005, the abuse of prescribed opiods, especially oxycodone extended release (OxyContin) and hydrocodone, has increased.[53] From Contracts may reduce abuse, but comparative studies provide conflicting results.[54] 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."

Withdrawal

Adding narcotic antagonists combined with alpha-adrenergic agonists may reduce withdrawal symptoms.[55]

Tolerance

N-methyl-d-aspartate receptor (NMDA) activation may lead to neuropathic pain and tolerance.[56][57] Methadone, which is a NMDA antagonist, may reduce tolerance.

Pruritis

Pruritis from histamine release may occur.[58] 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.

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  52. need to dig up the Cornell handbook
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