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.

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.

Opioid receptors

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 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. The American Pain Foundation is concerned that these recommendations consider the matter carefully, lest there be undertreatment with appropriate opioids.

Combination with aspirin and other non-narcotic agents was common before the widespread use of acetaminophen.

Selected opioids

Specific drug	Chemical class	Receptor action	Metabolism	Comments
Naturally occurring opium alkaloids
Morphine	morphine	mu, kappa (weak)
Codeine	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	morphine	mu (partial)
Hydromorphone (Dilaudid)	morphine	mu	Mostly hepatic	Oral bioavailability is approximately 24%
Buprenorphine	Thebaine	mu, antagonist of delta and kappa
Fully synthetic opioids
Meperidine	Meperidine	mu		Good oral absorption; toxic metabolite accumulates on prolonged use
Fentanyl	Meperidine	mu		Transdermal and transmucosal absorption
Methadone	methadone	mu		Good oral absorption. Bioavailability of methadone ranges between 36 to 100%. Different half-lives for analgesia and for blocking withdrawal
Tramadol	codeine	mu		Also inhibits monoamine oxidase; can raise norepinephrine and serotonin, and cause serotonin syndrome
Propoxyphene	propoxyphene	mu		D-isomer is analgesic; L-isomer is antitussive

Effectiveness

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

Narcotics are effective for both short (1-16 weeks) and long-term (6-24 months) use.

Narcotics, with long-term use, 80% of patients may have drug toxicity, most commonly gastrointestinal. In addition, substrance abuse and "aberrant medication-taking behaviors" may occur. Advice for using administering chronic narcotics and for treating acute pain among patients on chronic methadone is available.

Usage

Clinical practice guidelines are available.

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.

Adverse effects

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

Constipation

Constipation 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.) 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.

Dependency

Opioid agonist therapy includes buprenorphine and methadone. Although buprenorphine–naloxone may be less effective than methadone, it has more predictable dosing, and can be prescribed by qualifying office-based physicians.

Overdose

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

Substance abuse

With chronic use for treatment of pain, dependency may lead to substance abuse and "aberrant medication-taking behaviors" may occur.

Withdrawal

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

Tolerance

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

Pruritis

Pruritis from histamine release may occur. 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.