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University Department of Anaesthesia, Queen’s Medical Centre, University Hospital, Nottingham, UK
Address correspondence and reprint requests to Dr. G. J. Hobbs, Pain Management Centre, Queen’s Medical Centre, University Hospital, Nottingham, United Kingdom, NG7 2UH. Address email to greg.hobbs{at}mail.qmcuh-tr.trent.nhs.uk
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Abstract |
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IMPLICATIONS: The effect of several opioid analgesics on pupillary size has been studied. The results may be explained by differences in metabolism and pharmacokinetics of the drugs used. The data may be of use in defining a marker for the central effect of opioids and when assessing the degree of opioid toxicity.
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Introduction |
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Morphine and codeine are µ-opioid receptor agonists, although codeine has a lower receptor affinity than morphine. Tramadol, a novel opioid, derives only a third of its analgesic activity from opioid receptor stimulation; the remainder results from alteration of central transmission of norepinephrine and serotonin (5-HT) in the central nervous system (5). The pupillary effects of opioid drugs are usually observed within the first few minutes after IV administration (2). However, all of the opioid drugs used in this study have pharmacologically active metabolites that may contribute to their pupillary effects, and their contribution may be missed if the study was not long enough.
The aim of this study was to compare the pupillary effects of a single IV dose of morphine, codeine, tramadol, and placebo over a 6-h period.
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Methods |
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The study used a double-blind, crossover design. Volunteers attended four separate study sessions, each 2 wk apart. Treatments were allocated randomly so that volunteers received an IV bolus injection of placebo (10 mL of 0.9% w/v sodium chloride), morphine sulfate 0.125 mg/kg (Evans Medical Ltd., Leatherhead, Surrey, UK), codeine phosphate 1 mg/kg (Pharmacy Department, Queen’s Medical Centre, Nottingham, UK), or tramadol hydrochloride 1.25 mg/kg (Searle, Division of Monsanto PLC, High Wycombe, Buckinghamshire, UK) in 10 mL of 0.9% w/v sodium chloride at each session. The investigator who prepared the trial drugs for each session took no other part in the study; hence, the other investigators and volunteers did not know which drug had been administered. The subjects were seated or adopted a semireclined position and were allowed food, drink, and limited mobility after 4 h from the commencement of each session.
The pupil diameter of the volunteer’s right eye was measured using a pupil densitometer 3 times before drug administration (t = 0 min) and the value was used as a baseline measurement. Further measurements of pupil diameter were then made at 30, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min after drug administration. The mean of three consecutive measurements of pupil diameter was used in the analysis. Overall comparisons of the change in pupil diameter and percentage change in pupil diameter compared with baseline values for each dosage regimen were made using analysis of variance with repeated measures. Where these were statistically significant (P < 0.05), pairwise comparisons with the placebo data were made using the paired Student’s t-test. Statistical tests were performed using InStat (version 3.02) for Windows 95 (GraphPad Software, San Diego, CA).
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Results |
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Table 1 displays the mean pupil diameters during each study session. There was no significant change in pupil diameter after placebo (0.9% w/v sodium chloride) (P > 0.05). The initial pupil diameter was 5.5 ± 1.0 U. After injection of morphine or codeine there was a large decrease in pupil diameter during the initial 30 min of the study, as shown in Figure 1. Pupil diameter gradually returned to baseline values over the course of the remainder of the study, although this was more marked for codeine than morphine. At all time points after morphine administration the mean pupil diameters were significantly different than after placebo (P < 0.001), whereas after codeine the difference was only significant until 210 min compared with saline.
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Discussion |
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In humans, the major route of morphine metabolism is conjugation with glucuronic acid to form morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The predominant metabolite, M3G, has a very low affinity for the µ-opioid receptor (7,8), whereas M6G has a µ-opioid receptor affinity similar to morphine (9–11). Peak plasma concentrations of M3G (407 ± 100 nmol–1) and M6G (294 ± 54 nmol–1) are larger than the parent compound (273 ± 65 nmol–1) after IV administration (12). Elimination half-lives of both glucuronides (M3G 3.9 ± 1.5 hours; M6G 2.6 ± 0.7 hours) are also longer than morphine (1.7 ± 0.8 hours) (13). The initial large decrease in pupil diameter is most likely attributable to a direct miotic action of morphine at the µ-opioid receptors. However, the relatively slow return to baseline values is probably the result of a contribution from M6G.
Codeine and morphine are chemically related, codeine being 3-O-methylmorphine. The metabolic fate of codeine in humans is considerably more complicated than morphine because of the cytochrome P-450 mediated conversion to morphine and norcodeine. Hence, in addition to the formation of codeine-6-glucuronide (C6G), the predominant metabolite, there is also a small proportion of norcodeine, morphine, M3G, and M6G excreted in urine (2.2%, 0.6%, 2.1%, and 0.8%, respectively (14)). Like M3G, codeine has weaker affinity than morphine for µ-opioid receptors (15), which may explain why the initial decrease in pupil diameter is less than for morphine. The relative contribution of morphine and C6G to the µ-opioid receptor-mediated effects of codeine is controversial (16).
Although used in Europe for over 20 years, tramadol has only been recently marketed in the United States and the United Kingdom (5). In addition to weak agonist activity at the µ-opioid receptor, tramadol also inhibits the re-uptake of the neurotransmitters norepinephrine and 5-HT in the descending inhibitory pain pathways (17) and also facilitates 5-HT release (18). Tramadol is largely metabolized in the liver, using the same cytochrome P450 isoenzymes as required for codeine metabolism, to form a range of N- and O-demethylated compounds. The principal metabolite, O-desmethyltramadol (M1), is then able to undergo further conjugative reactions. Experimental models of pain have shown M1 to have an analgesic potency 2 to 4 times that of tramadol (5). Receptor binding studies also suggest that M1 has a much higher affinity than the parent compound at the µ-opioid receptor (19).
Distribution after an IV dose of tramadol occurs in two phases, the later phase having a peak plasma concentration 2 hours after drug administration.1 Although no pharmacokinetic data have been published, the peak concentration of the M1 metabolite is likely to occur even later. The slower accumulation of M1, and the longer distribution and elimination half-lives of tramadol may explain the different response compared with the other drugs.
Published data regarding the duration of opioid-induced miosis are limited. A similar decrease in pupil diameter to that observed in this study after IV injection of morphine has been reported (2). The maximum effect was observed after 4 minutes and this was maintained throughout the duration of the experimental period (30 minutes). Peacock et al. (3) studied the effect of an oral dose of codeine on pupil diameter and found that pupil diameter decreased significantly after codeine compared with placebo. Measurements of plasma codeine concentration were also made and it was concluded that the change in pupil diameter was related to the plasma codeine concentration (P < 0.05).
One study attempted to quantify the delay between plasma concentration versus time curve for M6G and the time course of its central opioid effects (20). As part of a single-blind randomized crossover study volunteers received either a bolus of morphine or M6G that was continued as an infusion. The decrease in pupil size after morphine administration was similar to that observed in this study. As the bolus dose was followed by an infusion, it is hard to determine whether time to minimum pupil size is comparable with this study. The transfer half-life of M6G (median, 6.4 hours) from plasma to effect site was longer than that for morphine (median, 2.8 hours) for each individual, although there was marked interindividual variability. Contradicting the predicted findings, M6G was found to be 22 times less potent than morphine, as assessed using the concentration at half-maximum effect values (EC50) of the sigmoid pupil size at maximum-constriction model, used to describe the concentration-response relationship. The reason for this finding is unclear.
The pupillary effects of tramadol have been in-vestigated previously in 22 healthy volunteers (21). A statistically significant small decrease in pupil size was reported 3 hours after administration, similar to that found in this study. IV codeine and IV tramadol have been compared as analgesics after neurosurgery (22). Adverse effects of both drugs were also studied, and pupil diameter was found to be significantly smaller after codeine than tramadol (P < 0.001); however, there was no indication as to when these measurements were made in relation to drug administration.
Önal and Tu
lular (23) studied the pupillary effects of morphine and several antidepressants with varying selectivity for norepinephrine and 5-HT receptors. Those antidepressants that primarily had noradrenergic effects (desipramine and amitriptyline) had a greater effect on pupil diameter than sertraline, a selective serotonin re-uptake inhibitor that had a larger effect on antinociception. Morphine had proportionally similar effects on pupil diameter and nociception.
Data from this study may be of use in a number of fields. Traditionally, the response to analgesic drugs has been difficult to assess because of the complex interaction of physiological, behavioral, and environmental factors. Changes in pupil diameter may be a potential marker for the central effect of opioids in pharmacokinetic—pharmacodynamic correlation studies. These data may also be of use when assessing opioid toxicity resulting from either therapeutic intervention or intentional overdose.
Interpretation of results after codeine administration is complicated by its complex metabolic fate. As a result of the genetic polymorphism of the cytochrome P-450 isoenzyme 2D6 (24), there may be some individuals who are unable to metabolize codeine to morphine and who experience reduced analgesia but retain considerable pupillary activity. Another study has contradicted this hypothesis, suggesting that the main pharmacologically active metabolite of codeine is C6G and not morphine (16).
The duration of the pupillary effect of opioids has been shown to be longer than the duration shown in previous studies. After an initial decrease, pupil diameter gradually returned towards baseline values after IV morphine and codeine administration. However, pupillary diameter was still decreasing 6 hours after IV tramadol administration. These data may have applications in further studies assessing the effect of opioids in the central nervous system and indicate the need to consider the role of pharmacologically active metabolites when performing such studies.
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Footnotes |
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References |
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lular I. The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice. Gen Pharmacol 1999; 33: 83–9.[ISI][Medline]
This article has been cited by other articles:
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  D. Hong, P. Flood, and G. Diaz The Side Effects of Morphine and Hydromorphone Patient-Controlled Analgesia Anesth. Analg., October 1, 2008; 107(4): 1384 - 1389. [Abstract] [Full Text] [PDF]
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J. P. Zacny Differential Effects of Morphine and Codeine on Pupil Size: Dosing Issues Anesth. Analg., February 1, 2005; 100(2): 598 - 598. [Full Text] [PDF]
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, 0.9% w/v sodium chloride (placebo); 
, morphine; 
, codeine; 
, tramadol.
