Background This review examines the evidence from published data concerning the incidence of moderate-severe and of severe pain after major surgery, with three analgesic techniques; intramuscular (i.m.) analgesia, patient controlled analgesia (PCA), and epidural analgesia. Methods A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Over 800 original papers and reviews were identified. Of these 212 papers fulfilled the inclusion criteria but only 165 provided usable data on pain intensity and pain relief. Pooled data on pain scores obtained from these studies, which represent the experience of a total of nearly 20 000 patients, form the basis of this review. Results Different pain measurement tools provided comparable data. When considering a mixture of three analgesic techniques, the overall mean (95% Cl) incidence of moderate-severe pain and of severe pain was 29.7 (26.4–33.0)% and 10.9 (8.4–13.4)%, respectively. The overall mean (95% Cl) incidence of poor pain relief and of fair-to-poor pain relief was 3.5 (2.4–4.6)% and 19.4 (16.4–22.3)%, respectively. For i.m. analgesia the incidence of moderate-severe pain was 67.2 (58.1–76.2)% and that of severe pain was 29.1 (18.8–39.4)%. For PCA, the incidence of moderate-severe pain was 35.8 (31.4–40.2)% and that of severe pain was 10.4 (8.0–12.8)%. For epidural analgesia the incidence of moderate-severe pain was 20.9 (17.8–24.0)% and that of severe pain was 7.8 (6.1–9.5)%. The incidence of premature catheter dislodgement was 5.7 (4.0–7.4)%. Over the period 1973–1999 there has been a highly significant (P Conclusions These results suggest that the UK Audit Commission (1997) proposed standards of care might be unachievable using current analgesic techniques. The data may be useful in setting standards of care for Acute Pain Services.

Effectiveness of acute postoperative pain management: I. Evidence from published data

UNLABELLED Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action, acting as both a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy and improve the tolerability profile of tramadol. In several comparative, well designed studies, oral and parenteral tramadol effectively relieved moderate to severe postoperative pain associated with surgery. Its overall analgesic efficacy was similar to that of morphine or alfentanil and superior to that of pentazocine. Tramadol provided effective analgesia in children and in adults for both inpatient and day surgery. Tramadol was generally well tolerated in clinical trials. The most common adverse events (incidence of 1.6 to 6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children. Tramadol also has a low potential for abuse or dependence. CONCLUSIONS The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom nonsteroidal anti-inflammatory drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well tolerated analgesic agent in the perioperative setting.

Tramadol: a review of its use in perioperative pain.

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

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Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Background. This study examines the evidence from published data concerning the adverse respiratory and haemodynamic effects of three analgesic techniques after major surgery; i.m. analgesia, patient-controlled analgesia (PCA), and epidural analgesia. Methods. A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Information relating to variables indicative of respiratory depression and of hypotension was extracted from these studies. Over 800 original papers and reviews were identified. Of these papers, 212 fulfilled the inclusion criteria but only 165 provided usable data on adverse effects. Pooled data obtained from these studies, which represent the experience of a total of nearly 20 000 patients, form the basis of this study. Results. There was considerable variability between studies in the criteria used for defining respiratory depression and hypotension. The overall mean (95% CI) incidence of respiratory depression of the three analgesic techniques was: 0.3 (0.1–1.3)% using requirement for naloxone as an indicator; 1.1 (0.7–1.7)% using hypoventilation as an indicator; 3.3 (1.4–7.6)% using hypercarbia as an indicator; and 17.0 (10.2–26.9)% using oxygen desaturation as an indicator. For i.m. analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 0.8 (0.2–2.5) and 37.0 (22.6–45.9)% using hypoventilation and oxygen desaturation, respectively, as indicators. For PCA, the mean (95% CI) reported incidence of respiratory depression varied between 1.2 (0.7–1.9) and 11.5 (5.6–22.0)%, using hypoventilation and oxygen desaturation, respectively, as indicators. For epidural analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 1.1 (0.6–1.9) and 15.1 (5.6–34.8)%, using hypoventilation and oxygen desaturation, respectively, as indicators. The mean (95% CI) reported incidence of hypotension for i.m. analgesia was 3.8 (1.9–7.5)%, for PCA 0.4 (0.1–1.9)%, and for epidural analgesia 5.6 (3.0–10.2)%. Whereas the incidence of respiratory depression decreased over the period 1980–99, the incidence of hypotension did not. Conclusions. Assuming a mixture of analgesic techniques, Acute Pain Services should expect an incidence of respiratory depression, as defined by a low ventilatory frequency, of less than 1%, and an incidence of hypotension related to analgesic technique of less than 5%.

Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data

Objective

Our objective was to quantify the extent and time course of the effects of morphine-6-glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects



Methods

In a double-blind, placebo-controlled, randomized, 3-way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of morphine-6-glucuronide or 26 to 66 mg of morphine as an intravenous bolus, followed by an infusion of the same medication for 18 to 64 hours Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0–999 mA) Pupil diameter and side effects were recorded concomitantly



Results

At the administered doses, morphine-6-glucuronide and morphine had comparable effects on pain tolerance, pupil diameter, and side effects The delay between the time course of the plasma concentrations and the time course of the effects was longer for morphine-6-glucuronide than for morphine (transfer half-life, 82 hours versus 26 hours for pain tolerance and 77 hours versus 28 hours for pupil diameter) The slope of the linear concentration versus effect relationship for pain tolerance was flatter for morphine-6-glucuronide than for morphine (005% versus 06% increase in pain tolerance per nanomole per liter of morphine-6-glucuronide and morphine at effect site, respectively) Morphine-6-glucuronide was less potent than morphine in producing pupil constriction (mean concentration at half-maximum effect, 745 nmol/L versus 264 nmol/L for morphine-6-glucuronide and morphine, respectively) In carriers of the mutated G118 allele of the μ-opioid receptor, the potency of the pupil-constricting effects of morphine-6-glucuronide and morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of morphine-6-glucuronide



Conclusions

Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers However, the high amounts of systemic morphine-6-glucuronide needed to produce the same effects as morphine suggest that morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of morphine



Clinical Pharmacology & Therapeutics (2003) 73, 107–121; doi: 101067/mcp20035

Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers

Background
Morphine-6-glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity. Morphine-3-glucuronide (M3G), the most prevalent metabolite, has minimal affinity for opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G.

Methods
We performed a double-blind placebo-controlled trial with 10 healthy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphine, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg/70 kg of M6G; all were give by slow intravenous bolus. Analgesia was assessed with the use of the submaximal ischemic pain model. The effects were quantified on numerical and visual analogue scales. Respiratory parameters and response to steady state 5% carbon dioxide challenge were assessed with spirometry, mass spectroscopy, and earlobe blood gas analysis.

Results
Morphine and M6G produced significant pain relief compared with placebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26). Pain relief with morphine and M6G were not significantly altered by M3G (P = .59 and P = .28, respectively). Significant and similar dysphoria and sedation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo (morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively).

Conclusions
M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine. (Clin Pharmacol Ther 2000;68:667-76.)

Clinical Pharmacology & Therapeutics (2000) 68, 667–676; doi: 10.1067/mcp.2000.111934

Krishna N Bakhshi

Papers

Randomized placebo‐controlled trial of the activity of the morphine glucuronides

Hypoxaemia after lower abdominal surgery: Comparison of tramadol and morphine