Pethidine (meperidine)

Observational studies

Hypotension, hypoxemia, and pain-related agitation were adverse events reported after co-administration of pethidine and midazolam for sedation and analgesia in children; no other events were reported [ ].

Comparative studies

The use of pethidine for pain control after abortion by manual vacuum aspiration was associated with more adverse reactions than if pethidine was not used in 113 patients, in whom three different analgesic regimens were compared: diclofenac + paracervical block, pethidine + diclofenac, and pethidine alone [ ]. All three regimens achieved similar analgesia, but adverse reactions were more common in those in whom pethidine was used. Nausea and dizziness were significantly more common.

Placebo-controlled studies

In a double-blind, randomized, placebo-controlled study, 40 patients who were scheduled for elective cesarean section under spinal anesthesia were given intrathecal 0.5% hyperbaric bupivacaine 2 ml together with either 5% pethidine 0.2 ml or isotonic saline [ ]. The pethidine group had a significantly greater incidence of intraoperative nausea or vomiting, with significantly better immediate postoperative analgesia, which was not sustained 4 hours after surgery.

In a randomized, controlled study in 611 mothers, 310 were randomized to intramuscular pethidine up to 300 mg and 301 to epidural 0.25% bupivacaine 10 ml with an infusion of 0.125%–0.25% bupivacaine [ ]. There were no significant differences in analgesic efficacy, adverse effects, or the incidence of backaches.

The analgesic and adverse effects of pethidine, metoclopramide, and the combination have been compared in a randomized, double-blind, controlled study in the emergency treatment of acute primary vascular and tension-type headaches in 366 patients [ ]. The drug regimens were:

• intravenous metoclopramide 10 micrograms + intramuscular placebo;

• intramuscular pethidine 50 micrograms + intravenous placebo;

• intravenous metoclopramide 10 micrograms + intramuscular pethidine 50 micrograms;

• intravenous placebo + intramuscular placebo.

Pethidine was more effective than placebo, but metoclopramide was the most effective. There were adverse reactions in 126 patients (38%); the most common were drowsiness or light sedation (20%). The adverse reactions profile was significantly worse in those given pethidine.

Systematic reviews

There has been a systematic review of the postoperative analgesic efficacy and adverse effects of pethidine and ketorolac compared with placebo in published randomized, controlled, double-blind studies [ ]. The authors reviewed studies of moderate to severe postoperative pain relief and the use of single doses by injection (intravenously or intramuscularly) or orally. Studies of epidural, intrathecal, or intravenous administration using patient-controlled analgesia were excluded. Of the 24 placebo-controlled pethidine studies, only eight met the inclusion criteria and these generated 10 pethidine versus placebo comparisons and 254 patients given pethidine 50 mg or 100 mg intramuscularly. No studies of oral or intravenous pethidine at any dose met the inclusion criteria. Only the eight comparisons of pethidine 100 mg versus placebo (n = 203) had sufficient information available for analysis of adverse reactions. The overall conclusion was that opioids carry a small but finite risk of serious adverse reactions, such as respiratory depression, and a greater risk of minor adverse reactions than single-dose injected or oral NSAIDs like ketorolac. Analgesia from the injected opioid or NSAID was equivalent to that achieved with oral NSAIDs. For those who cannot swallow, the choice is injected opioids like pethidine.

Cardiovascular

When used for sedation in children undergoing esophagogastroduodenoscopy, hypoxia with dysrhythmias was more likely to occur with a combination of pethidine and diazepam than with pethidine and midazolam [ ].

• A 70-year-old patient with a metastatic carcinoid tumor of the liver presented with a hypertensive crisis after being given pethidine 10 mg/hour by continuous intravenous infusion [ ]. The patient remained hypertensive with a systolic blood pressure of 210 mmHg, even after chemoembolization of the tumor. The blood pressure fell when pethidine was withdrawn and nitroprusside was given. The serum 5HT concentration was 15 μmol/l (reference range 0.17–0.26) and the urine 5-hydroxyindoleacetic acid concentration was 1311 mg/g of creatinine (reference range less than 10).

The authors postulated that the hypertensive crisis had occurred from the release of 5HT from the tumor and blockade by pethidine of 5HT re-uptake.

Nervous system

Cases of severe reversible neurotoxicity and parkinsonism are on record [ , ]. Severe nervous system syndromes may also result from interactions (see the monograph on Opioid receptor agonists).

Although seizures are uncommon, several cases have been reported, including when pethidine was used in PCA. The metabolite norpethidine is considered to be of significant importance in provoking seizures. Risk factors are renal insufficiency, sickle-cell anemia, high doses of pethidine, and concurrent administration of phenothiazines or drugs that induce hepatic enzymes [ ]. Myoclonus can occur [ ]. Norpethidine is twice as likely as pethidine to cause convulsions. The seizures occur at a norpethidine concentration range of 0.38–9.9 μg/ml, and only few reports have described convulsions within the first 24 hours of pethidine treatment.

• A 35-year-old woman, who was admitted for elective laparotomy and ileostomy formation was given patient-controlled analgesic with pethidine for postoperative analgesia [ ]. The device was set to deliver 20 mg of pethidine with a 5-minute lock-out period and no hourly limit. At 4 hours postoperatively she did not have pethidine-related neurotoxicity, but at 23 hours she had myoclonic jerks and facial twitching followed by a brief generalized tonic-clonic seizure and postictal sequelae. The pethidine was withdrawn and there was no further seizure activity. She had taken a total of 2700 mg. The norpethidine concentration was 1.8 μg/ml.

• A 55-year-old woman developed severe abdominal pain, vomiting, diarrhea, and dysuria. A provisional diagnosis of pyelonephritis was made, and she was given intravenous pethidine in gradually increasing doses until day 4 (cumulative dose 2125 mg), when she had a seizure lasting 1 minute [ ]. The pethidine was withdrawn and replaced with buprenorphine, with no further complications.

• A 34-year-old woman who had undergone left hip revision surgery was first given patient-controlled hydromorphone, which was changed to pethidine 15 micrograms every 6 minutes as needed on the third postoperative day and received 1500 micrograms of pethidine over the first 36 hours [ ]. On day five she had a witnessed generalized tonic-clonic seizure. Pethidine was withdrawn and no further seizures were witnessed.

Two of three patients with seizures due to norpethidine toxicity [ ] had renal disease.

• A 46-year-old woman with previous extensive urological problems, including ureteric stricture and recurrent urinary tract infections, was given pethidine in a total cumulative dose of 1500 mg postoperatively over 12 hours when she presented with a single tonic-clonic seizure that lasted 30 seconds. The pethidine concentration was 1200 ng/ml and the norpethidine concentration 2100 ng/ml.

• A 72-year-old patient with end-stage renal insufficiency undergoing peritoneal dialysis developed myoclonic contractions and a generalized tonic-clonic seizure 48 hours after having been given pethidine in a total cumulative dose of 250 mg intravenously and 600 mg orally. The neurotoxicity resolved after withdrawal of pethidine and 4 hours of hemodialysis.

• A 2-month-old boy presented with muscle rigidity of the arms and legs, catatonia, and an exaggerated startle reflex after being erroneously given a single dose of pethidine 1 mg/kg. The symptoms subsided without any active intervention.

Two case reports have highlighted the potential danger of injecting pethidine into the lateral thigh region, which can cause injury to the femoral nerve branch to the vastus lateralis, causing muscle atrophy [ ].

In a retrospective survey of 355 medical records of patients who received intravenous PCA pethidine between 1988 and 1994 the mean consumption by patients who had used over 600 mg/day of pethidine was 13.3 mg/kg/day in asymptomatic patients and 16.9 mg/kg/day in the 2% of patients who presented with central nervous system excitatory signs and symptoms (muscle twitches, jitteriness, agitation, and hallucinations) [ ]. The authors recommended a maximum safe dose of pethidine by PCA of 10 mg/kg/day for no more than 3 days.

Pethidine 80 mg given intravenously over 20 minutes in 100 ml of saline to an otherwise healthy 29-year-old woman with low back pain caused reversible retrograde amnesia lasting about 3 hours and disorientation in time, place, and person [ ].

A 27-year-old man with a history of acute myeloid leukemia developed serotonin syndrome after being given for sepsis and pethidine for rigors [ ]. He received pethidine 90 minutes after the third dose of linezolid and developed the serotonin syndrome about 30 minutes later. The symptoms reversed when pethidine was withdrawn.

Gastrointestinal

A study in which it was intended to recruit 90 women in labor for a comparison of intrathecal bupivacaine 2.5 mg, fentanyl 25 microgram, pethidine 15 mg, and pethidine 25 mg was stopped prematurely after only 34 had been recruited, because of a significant increase in the incidence of nausea and vomiting in the patients who received the two doses of pethidine [ ].

The prevalence of nausea after parenteral morphine (n = 37) and pethidine (n = 156) was measured in a prospective study in two groups matched for age, sex, weight, and potency of the opioid administered [ ]. The average total dose of morphine was 8.4 mg and of pethidine 96 mg. None of those given morphine had nausea, compared with two of those given pethidine. This was a pilot study and a more rigid randomized double-blind study would be helpful. Equally, a more objective study endpoint needs to be considered in future studies rather than “nausea”, which is subjective and may not be interpreted similarly by all patients.

Non-steroidal anti-inflammatory drugs have been compared with opioids in the treatment of acute renal colic in a meta-analysis of 20 studies [ ]. Seven different opioids were studied. In most of the studies there was a higher incidence of adverse events in patients who took opioids. Pooled analysis showed significantly more vomiting in those who took opioids, particularly pethidine. No serious adverse events were reported and adverse event rates did not vary with dosage.

Musculoskeletal

Muscle rigidity after spinal anesthesia occurred in a 17-year-old man admitted for emergency appendicectomy [ ]. During the operation, he developed shivering and was given intravenous diazepam 5 mg and pethidine 50 mg. Minutes later he developed severe rigidity in the neck, masseters, arms, thoracoabdominal region, and thighs.

Immunologic

Pethidine causes histamine release [ ]. Of 16 patients given pethidine (mean dose 4.3 mg/kg), five had signs of the effects of histamine (hypotension, tachycardia, erythema) and raised histamine concentrations.

• A 42-year-old patient presented with generalized pruritus, erythema, urticaria, facial angioedema, dysphagia, dysphonia, and dizziness 15 minutes after a single intramuscular dose of pethidine 100 mg for severe renal colic [ ]. Prick tests and intradermal tests with pethidine and other compounds confirmed an allergic reaction to pethidine.