Drug Profiles:
Meperidine Hydrochloride
AKA Demerol®
Interpol* AKA Pethidine

CAUTION: Federal law prohibits dispensing without prescription.

* Ok, Interpol is really not involved here, but for those of us outside the United States they know Demerol® as Pethidine, so there you go!

Demerol® is for moderate to severe Migraine pain management. Migraineurs find Demerol® is a useful therapy when taken with a small amount of food and then laying down in a dark and quite room. It also works well when taken with an anti-nausea medication. ER’s commonly use the injectable version of this drug with prochlorperazine (Compazine®) to treat run away severe Migraine. Because it is very strong narcotic, it should be used when abortive medications fail (also know as a rescue medication in Migraine circles) or when abortives are not appropriate (such as with Basilar or Hemiplegic Migraine).

Description:

Meperidine hydrochloride (also known as pethidine outside the US) is a synthetic opiate agonist belonging to the phenylpiperidine class. Other members of this group include alfentanil, diphenoxylate, fentanyl, loperamide, and sufentanil. The chemical structure of meperidine is similar to local anesthetics. Meperidine is recommended for relief of moderate to severe acute pain and has the unique ability to interrupt postoperative shivering and shaking chills induced by amphotericin B. Meperidine has also been used for intravenous regional anesthesia, peripheral nerve blocks and intraarticular, epidural and spinal analgesia. A high incidence of side effects limits the utility of meperidine in these situations. According to the Agency for Health Care Policy and Research Clinical Practice Guideline for acute pain management in operative or medical procedures and trauma, meperidine is recommended only for use in very brief courses in patients who are healthy and/or have problems with other opiate agonists. Meperidine is considered a second-line agent for the treatment of acute pain. Meperidine is commonly underprescribed in terms of dose and interval. Meperidine is metabolized to normeperidine, a compound capable of inducing seizures at high concentrations. Meperidine is not recommended for the treatment of chronic pain because of the risk of seizures with repetitive dosing and its short duration of action. Meperidine is often used as a rescue medication for treatment of Migraine, meaning used for controlling severe Migraine when a Migraineur dose not respond to abortive treatments or the Migraineur cannot use effective abortive regimes when they are contraindicated. Meperidine is available in both oral and parenteral forms and was approved by the FDA and marketed in 1942.

Mechanism of Action:

Meperidine is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Meperidine has more affinity for the kappa-receptor than morphine. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase₃ C (PLC)-inositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca).

Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ₂-, delta-, kappa-receptors) and higher levels in the CNS (µ₁- and kappa₃ receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opiates close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (µ and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opiates decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline. Opiates also modulate the endocrine and immune systems. Opiates inhibit the release of vasopressin, somatostatin, insulin and glucagon.

The stimulatory effects of opiates are the result of "disinhibition" as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms including differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

Clinically, stimulation of µ-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Meperidine's superiority over other opioid agonists in the treatment of post-operative shivering is probably related to its kappa-receptor activity, although the exact mechanism is not known. Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Respiratory depression is caused by direct action of opiate agonists on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention.

Several other clinical effects occur with opiate agonists including cough suppression, hypotension, and nausea/vomiting. The antitussive effects of opiate agonists are mediated through direct action on receptors in the cough center of the medulla. Cough suppression with meperidine occurs at doses necessary for analgesia. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor center in the medulla. Intravenous meperidine results in more histamine release than equipotent doses of morphine, fentanyl or sufentanil. Induction of nausea and vomiting possibly occurs from direct stimulation of the vestibular system and/or the chemoreceptor trigger zone.

Pharmacokinetics:

Meperidine is administered via the oral or parenteral routes. When administered orally, it undergoes extensive first-pass metabolism. Oral bioavailability increases to 80–90% in patients with hepatic impairment, compared with 50–60% in patients with normal hepatic function. Meperidine is less than one-half as effective when given orally as opposed to parenterally and it is recommended not to give meperidine via this route. After oral administration the onset of analgesia is within 15 minutes and peak effects occur in 60–90 minutes. Following subcutaneous or IM administration, onset of analgesia occurs within 10–15 minutes and peak effects occur within 1 hour. When given intravenously, the onset of analgesia is noted within 1 minute and the time to peak effects is 5–7 minutes. The duration of meperidine-induced analgesia is 2–4 hours but this decreases with chronic dosing. Protein binding is 65–75%, primarily to albumin and alpha-1-acid glycoprotein. Meperidine is distributed widely, and it crosses the placenta and distributes into breast milk.

Following epidural administration of meperidine, the onset of analgesia is 5–10 minutes with a peak effect in about 15–30 minutes. The duration of analgesia is about 4–6 hours. The relative lipid solubility of meperidine as compared to morphine is 30:1.

Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. In patients with normal hepatic and renal function, meperidine half-life is 3–5 hours; in patients with hepatic dysfunction, it is extended to 7–11 hours. Normeperidine, an active metabolite of meperidine, is about half as potent as meperidine, but it has twice the CNS stimulation effects. The half-life of normeperidine is substantially longer (15–30 hours) than meperidine and is further increased in patients with renal dysfunction (> 30 hours). Accumulation of this metabolite after repeated or high doses in patients with hepatic or renal impairment will occur. Patients with normal urine pH excrete about 30% as the active metabolite and about 5% as unchanged parent drug. Acidification of the urine greatly enhances excretion of both meperidine and normeperidine.