Demerol: Is It the Best Analgesic?

Introduction

"Demerol is an old, lumbering dinosaur which must be taken out of use in order that effective pain control can become a reality.”

Dr. J. Davis Daniels
The Passing of Demerol¹

One of the most commonly used opioid analgesics on the market is meperidine (DEMEROL). Eisendrath, et al., claimed in 1987 that meperidine was the most widely used opioid analgesic in the US, prescribed by approximately 60% of physicians for acute pain and by 22% for chronic pain.² Of the top 10 drugs mentioned by general surgeons in 2004, based on projected data from a survey of general surgeons, Demerol injection was third on the list.³

Meperidine is considered to be an inappropriate medication for patients over the age of 65 based on the Beers criteria,⁴ yet a 2006 study that examined the use of meperidine in patients over the age of 65 in two urban hospitals found that meperidine was administered to approximately one in eight older surgical patients at both institutions. In addition, surgical patients were more likely than medical patients to receive a dose of meperidine.⁵

Meperidine was initially produced in 1939 for its anticholinergic effects, but its analgesic properties were discovered soon thereafter. Morphine, at that time, was associated with many problems such as constipation, urinary retention, potential for dependency and respiratory depression while meperidine was thought to be an analgesic without these problems.⁶ But initial studies demonstrating the analgesic efficacy of meperidine were mostly case reports and not double-blind, randomized, controlled trials in specific populations. Subsequent comparative studies failed to demonstrate any advantages of meperidine over comparable doses of other analgesics.⁷ In fact, studies found that the analgesic effects of meperidine are not pronounced, and that meperidine has unique side effects including serotonergic crisis and toxicity by its metabolite, normeperidine.

Central Nervous System Effects

Meperidine is a phenylpiperadine opioid agonist analgesic with anticholinergic, serotonergic, and noradrenergic effects. Meperidine is metabolized in the body by two different pathways. The predominant pathway is hepatic carboxylesterase metabolism to meperidinic acid, an inactive metabolite. However, the most clinically significant pathway is N-demethylation by the cytochrome P-450 system producing normeperidine, a nonopioid active metabolite.

Normeperidine has half the analgesic potency of meperidine but two to three times the potency as a central nervous system (CNS) excitatory agent. The accumulation of normeperidine has been shown to cause anxiety, hyperreflexia, myoclonus, mood changes, and seizures within 24 hours.⁸ The bioavailability and half-life of orally administered meperidine are increased in patients with cirrhosis. For that reason, the use of meperidine in patients with cirrhosis is contraindicated due to increased risk of toxicity from accumulation of meperidine and normeperidine. Meperidine is also contraindicated in patients with renal impairment because normeperidine can accumulate in these patients.

The seizure activity produced by normeperidine makes meperidine stand out from other opioid analgesics. Seizures caused by normeperidine accumulation are a non-opioid effect; therefore, analgesic antagonists such as naloxone (NARCAN) will not stop this activity. Adverse drug reaction reports to PA-PSRS provide classic examples of this problem.

A patient received a 50 mg dose of Demerol for pain, which was not the first dose given to this patient. Shortly, the patient’s roommate notified the nurse that the patient had fallen on the floor. The nurse found the patient on floor, face down and seizing. The patient was not responsive to verbal or physical stimuli, was turned over and placed in bed. Oxygen was applied and the patient slowly began responding after 3-5 minutes. Patient had a suspected history of seizures possibly associated with higher doses of Demerol.

A patient was ordered meperidine 100 mg I.M. every 3 hours as needed. Over a period of three days the patient received a total of 1900 mg of meperidine, which led to the patient developing seizures.

After receiving meperidine for a procedure, the parents of a pediatric patient reported to the recovery room nurse that the patient was twitching. They stated that the patient was not doing this before. The nurse observed rapid eye movement and seizure-like head movements. The patient’s arms were rigid and he was unable to extend his arm voluntarily, but was able to follow verbal commands. Approximately 30 minutes later no seizure like activity noted.

Clinically, the predominate side effect that differentiates meperidine from the other opioids is its neurotoxicity. Meperidine has been implicated in “Serotonin Syndrome.”⁹ Serotonin Syndrome (SS) is thought to be caused by high levels of serotonin (5-HT) in the CNS. Most cases of SS reported in the literature were associated with patients taking two or more medications that increase CNS serotonin levels by different mechanisms such as monoamine oxidase inhibitors (MAOI) used in conjunction with meperidine, tricyclic antidepressants, or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants.¹⁰ Examples of commonly used SSRI antidepressants, also known as 5-HT-selective reuptake inhibitors, include fluoxetine (PROZAC), paroxitine (PAXIL), sertraline (ZOLOFT), and citalopram (CELEXA).

Common symptoms of SS that are similar with toxicity due to normeperidine evident in adverse drug reaction reports involving meperidine submitted to PA-PSRS include: altered mental status, agitation, shaking, tremors, dystonic cramping in legs, and restlessness. A more extensive list of common SS symptoms is presented in "Symptoms Associated with Serotonin Syndrome."

The Institute for Safe Medication Practices (ISMP) has reported on a case in which a 59-year-old woman experienced Seratonin Syndrome after meperidine PCA was discontinued due to hallucinations and agitation. When her symptoms worsened with IV lorazepam, a pharmacist investigated treatment options for what he thought was normeperidine metabolite accumulation, but he could find little information. He then called the Poison Control Center. After learning that the patient also was taking ZOLOFT (sertraline), Poison Control suggested that the patient might be suffering from Seratonin Syndrome. The nurse confirmed that the patient had several telltale symptoms (hyperreflexia, diaphoresis, diarrhea, disorientation, confusion, hallucinations). Cyproheptadine 4 to 8 mg orally every four hours was recommended, and the patient improved dramatically within the next several hours after receiving the drug.¹²

In a study to determine the cumulative doses of opioid agonists, Walker and Zacny called meperidine the most intoxicating of the narcotics tested. Meperidine had the largest mean peak ratings of “confused,” “high,” “drunk,” “floating,” “coasting,” and “difficulty concentrating.” They stated that meperidine had the most intense effects, but they were short lived, lasting approximately 5 minutes.¹³

Another problem with meperidine is the anticholinergic effect of meperidine owing to its blockade of muscarinic/acetylcholine receptors. Common side effects of anticholinergics include blurring of vision, constipation, agitation, confusion, delirium, and disorientation.

Analgesic Effects

Despite its popularity as an analgesic, numerous studies have shown the ineffectiveness of meperidine compared to other medications used for pain relief. Austin, et al., demonstrated the limitations of a scheduled dose of 75 mg of meperidine every 6 hours, with patients not achieving significant levels of pain relief for more than 24 hours after surgery.¹⁴ During the initial post-dose 4-hour period, patients only received partial pain relief for 30 minutes.

In a comparison of three equipotent doses of meperidine with morphine delivered via PCA, Plummer, et al., found that the level of analgesia at rest following major abdominal surgery provided by both drugs was similar, but that on movement morphine provided better analgesia at the three doses that were compared in the study. ¹⁵

In another PCA study, Bahar, et al., noted that overall pain relief was similar, but that pain on movement, after deep inspiration or coughing, and at rest was better with morphine than meperidine.¹⁶ Vetter demonstrated in children using PCA devices that morphine produced significantly better pain scores than meperidine with no difference in the side-effect profiles. Further, the anxiolytic effect of morphine reduced the distress and suffering of the children when compared with meperidine.¹⁷

Jasani, et al., compared the therapeutic effects of 50 mg of meperidine to 1 mg of HYDROmorphone for the treatment of ureteral colic and demonstrated that with HYDROmorphone, patients needed fewer breakthrough medications (31% versus 68%), fewer intravenous pyelograms (28% versus 54%), and fewer hospital admissions (25% versus 49%). This study also reported improved analgesia with HYDROmorphone. Clinically, patient outcomes were significantly better with HYDROmorphone, and it provided more cost-effective treatment.¹⁸

In a study comparing the analgesic efficacy of IM doses of ketorolac, meperidine, and placebo after major orthopedic surgery, DeAndrade, et al., showed that ketorolac was significantly more effective than meperidine in duration of action and in the number of patients requiring additional medication 6 hours after the first dose. In addition, ketorolac was associated with significantly lower percentages of patients reporting adverse drug events.¹⁹

Not only has meperidine been shown to be an inferior analgesic compared to other opioids; it is also characterized by a limited duration of action. This effect may have some utility for short-duration procedures but is less than optimal for treating situations in which pain is of longer duration.²⁰

Conclusion

Given the reports in the literature, its potential for seizures, its effects on the central nervous system, and its anticholinergic effect, meperidine may not be the optimal analgesic for the treatment of pain. The euphoric effects are reported to be more pronounced than with other analgesic agents, and it is the only agent associated with negative effects on mood. It has been shown to be a less effective analgesic than other agents with a capacity to cover mild to moderate pain.

The anticholinergic effect decreases the amount of secretions and thus enhances endoscopic procedures, and if used for moderate pain for less than 24 hours, practitioners can avoid the side-effect profile. The use of meperidine requires careful patient selection, since the Beers criteria classifies it as an inappropriate medication for individuals over 65 years of age. In addition, its use requires vigilant monitoring for neuron-excitatory effects and tracking of dosage to reduce the risk of neurotoxicity, as well as awareness of concomitant or recent use of serotonergic drugs to prevent potentially fatal drug interactions.

Since other opioid agonist analgesics have similar analgesic efficacy, lower risk of neurotoxicity at usual therapeutic doses, and lower risk for Serotonin Syndrome due to drug interactions, your facility may want to consider limiting the use of meperidine to those situations in which the benefits outweigh the risks.

Notes

1. Daniels D. The Passing of Demerol. [online.] 2006 May 19. Available from Internet. http://ruralnet.marshall.edu/pain/demerol.htm  
2. Eisendrath SJ, Goldman B, Douglas J, et al. Meperidine-induced delerium. Am J Psychiatry 1987;144:1062–5.
3. American College of Surgeons. Vital signs: Top 10 drugs mentioned by General Surgeons in 2004. Surgery News. (1)6:1.
4. Pennsylvania Patient Safety Reporting System (PA-PSRS).  The Beers Criteria: Screening for Potentially Inappropriate Medications in the Elderly. PA-PSRS Patient Safety Advisory. 2005 Dec;2(4):11-15.
5. Kornitzer BS, Manace LC, Fischberg DJ, et al. Prevalence of meperidine use in older surgical patients. Arch Surg. 2006 Jan;141(1):76-81.
6. Batterman RC. Demerol: a new synthetic analgesic: its indications as a substitute for morphine. Conn State Med Journal 1944;8:13–7.
7. Latta KS, Ginsberg B, Barkin RL, et al. Meperidine: A Critical Review.  Am. J. Ther. Jan/Feb 2002;9(1):53.
8. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1983;13:180–5.
9. Weiner AL. Meperidine as a potential cause of serotonin syndrome in the emergency department. Acad Emerg Med 1999; 6:156–8.
10. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13.
11. Nolan S, Scoggin AJ. Serotonin Syndrome: recognition and management. [online.] 2006 May 24. Available from Internet.    http://www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/acf2fa6.htm
12. Institute for Safe Medication Practices. Safety Brief. Medication Safety Alert! 6 Mar 2002;7(5):1.
13. Walker DJ, Zacny ZP. Subjective, psychomotor, and physiological effects of cumulative doses of opioid agonists in healthy volunteers. J Pharmacol Exp Ther 1999;289:1454–64.
14. Austin KL, Stapleton JV, Mather LE. Relationship between blood meperidine concentrations and analgesic response: a preliminary report. Anesthesiology 1980;53:460–6.
15. Plummer JL, Owen H, Isley AH, et al. Morphine patient-controlled analgesia is superior to meperidine patient-controlled analgesia for postoperative pain. Anesth Analg 1997;84797–9.
16. Bahar M, Rosen M, Vickers MD, et al. Self-administered nalbuphine, morphine and pethidine comparison, by intravenous route, following cholecystectomy. Anesthesia 1985;40:529–32.8.
17. Vetter TR: Pediatric patient-controlled analgesia with morphine versus meperidine. J Pain Symptom Manage 1992;7:204–8.
18. Jasani NB, O'Connor RE, Bouzoukis JK: Comparison of hydromorphone and meperidine for ureteral colic. Acad Emerg Med 1994;1:539–43.
19. DeAndrade. Ketorolac Versus Meperidine for Pain Relief After Orthopaedic Surgery. Clin Orthop; 1996;325;302–12.
20. Latta KS, Ginsberg B, Barkin RL. Meperidine: A Critical Review. American Journal of Therapy Vol.9(1).Jan/Feb 2002:61.

Supplemental Material

Symptoms Associated with Serotonin Syndrome

Mental Status Changes

• Confusion (51%)
• Agitation (34%)
• Hypomania (21%)
• Anxiety (15%)
• Coma (29%)

Cardiovascular

• Sinus tachycardia (36%)
• Hypertension (35%)
• Hypotension (15%)

Gastrointestinal

• Nausea (23%)
• Diarrhea (8%)
• Abdominal pain (4%)
• Salivation (2%)

Motor Abnormalities

• Myoclonus (58%)
• Hyperreflexia (52%)
• Muscle rigidity (51%)
• Restlessness (48%)
• Tremor (43%)
• Ataxia/incoordination (40%)
• Shivering (26%)
• Nystagmus (15%)
• Seizures (12%)

Other

• Diaphoresis (45%)
• Unreactive pupils (20%)
• Tachypnea (26%)
• Hyperpyrexia (45%)

Source: U.S. Pharmacist. Reprinted with permission.

Self-Assessment Questions

The following questions about this article may be useful for internal education and assessment. You may use the following examples or come up with your own.

1. Which metabolite of meperidine is associated with seizure-producing neurotoxic side effects?
1. Meperidinic acid
2. Normeperidine
3. Hydroxynormeperidine
4. None of the above
2. What side effects are associated with the accumulation of normeperidine?
1. Myoclonus
2. Anxiety
3. Hyperreflexia
4. Seizures
5. All of the above
3. All of the following have been demonstrated in studies involving meperidine except?
1. Morphine produced better pain scores than meperidine
2. Ketorolac was more effective than meperidine in duration of action
3. Meperidine produced significantly better pain scores than morphine with children using PCA devices
4. Hydromorphone demonstrated fewer breakthrough medications were needed and improved analgesia than meperidine
4. What symptoms are associated with Serotonin Syndrome?
1. Agitation
2. Confusion
3. Myoclonus
4. Tremor
5. All of the above
5. Meperidine is an appropriate medication to be prescribed to any patient over 65 years of age.
1. True
2. False