Hydromorphone is a semisynthetic derivative of morphine. Both drugs exert their analgesic effect at μ-opioid receptors1 and have typical opioid-associated side effects including respiratory depression, nausea, vomiting, and pruritus. Although there is a “clinical lore” among health care providers asserting that treatment with hydromorphone results in improved pain control and fewer adverse side effects, morphine continues to be the first-line medication for postoperative pain control with patient-controlled analgesia (PCA). An article derived from Wikipedia on January 1, 2008, states “Hydromorphone’s side effect profile, explored in greater detail in the section on side effects, is closer to that of dihydromorphine than that of morphine and importantly produces less nausea and vomiting and fewer histamine-related side effects than morphine as a result.” This idea can also be found in the peer-reviewed scientific literature.2 If either drug were consistently found to have significantly fewer side effects with equal efficacy, it should clearly be the drug of choice.
Differences between the clinical pharmacology of the two drugs could theoretically result in such differences. A bolus of hydromorphone reaches its peak effect in approximately 20 min, whereas an equivalent morphine bolus will require 94 min to reach peak. Within a standard 6–10 min dosing interval used with PCA, the hydromorphone dose will be close to peak, whereas the morphine bolus will not. Thus, it would be possible to stack morphine doses with PCA, and a relative overdose could lead to more side effects. Furthermore, morphine has been shown to induce histamine release while hydromorphone does not.3,4 Histamine release might increase the likelihood of pruritus.
Clinical studies comparing the use of IV morphine and hydromorphone are scarce and most were designed for indications other than postoperative pain5,6 or did not use PCA methodology.7–10 We compared morphine and hydromorphone treatment via PCA for acute or postsurgical pain because these drugs are commonly used in this manner after surgery and the relatively high postoperative doses are more likely to be associated with side effects. In this prospective randomized, double-blind trial, we compared the efficacy of morphine and hydromorphone given at equianalgesic doses using pain report, reduction in pupil size, and side effect profiles. Because of the wide range of reported equianalgesic values reported in the literature,11,12we measured drug-induced miosis with pupillometry as a measure of μ-opioid receptor activation.
This double-blind, randomized, prospective trial was designed to compare the side effect profile of morphine and hydromorphone used for PCA after general surgery. The trial was approved by the IRB of the Columbia University Medical Center. Written consent was obtained from all subjects.
Fifty patients were enrolled and followed for 8 h after surgery. All subjects were between the ages of 18 and 60 yr, in general good health (ASA class I and II) and scheduled to undergo lower abdominal or pelvic surgery with planned use of PCA. Exclusion criteria were preoperative pain or use of pain medication, morbid obesity (body mass index >30), diagnosis of sleep apnea, hepatic or renal disease, alcoholism, or the use of medications that would affect opioid pharmacodynamics, including rifampin, barbiturates, phenytoin, and benzodiazepines.
Patients were assigned by computer-generated randomization to receive either morphine or hydromorphone PCA after surgery. During surgery, all patients were anesthetized with a volatile anesthetic and were treated with 0.1–0.2 mg/kg morphine or the equivalent of another long-acting opioid. All subjects were treated with a prophylactic dose of 4 mg ondansetron during anesthesia. The anesthetic procedure was not otherwise standardized. Study medications were prepared by the research pharmacy in 150-mL containers of either 1 mg/mL of morphine or 0.2 mg/mL of hydromorphone, the standard concentrations normally used in our institution. The patient, investigator, and health care staff were blinded to the treatment group. PCAs were prepared and administered immediately after surgery according to the following protocol: 1 mL demand dose, 6 min lockout, and 10 mL hourly limit, with 3 mL boluses for breakthrough pain to a limit of 4 boluses per hour. The demand dose could be increased to 1.5 mL for inadequately controlled pain. Ketorolac 30 mg was given for breakthrough pain if their pain was inadequately controlled with the higher doses of opioids given through the PCA.
Data were collected by the research assistant 1 and 8 h after surgery. Pain was assessed at rest and with movement using a verbal numerical rating scale (NRS) from 0 to 10 (0 was no pain and 10 was the worst pain imaginable). The amount of morphine or hydromorphone used via PCA was recorded at these times. The pupil sizes were measured at baseline (preoperative) and 1 and 8 h after surgery using a Colvard pupillometer (Oasis; Glendora, CA). The pupillometer had a resolution of 0.5 mm. Ambient light was controlled during the pupil measurements to between 3.0 ± 2 electron volts measured with a light meter in incident mode (Sekonic Flashmate L-308s; Tokyo, Japan). Measurements were taken from each eye and the results were averaged.
Sedation, nausea, and pruritus were recorded as side effects. The Ramsey scale was used as a measure of sedation.13 An incidence of nausea and pruritus was measured in addition to magnitude on a NRS (0 = none, 10 = the worst). Antiemetic medication (IV ondansetron, dolasetron, or metoclopramide) and antipruritic medication (IV diphenhydramine) were given according to the standard PCA protocol and recorded at each data collection period. Patient satisfaction with pain control was recorded on a NRS at 24 h with 0 = extremely dissatisfied, 5 = neutral, and 10 = most satisfied. Finally, we recorded arterial blood pressure and heart rates of all patients at our measurement points.
The study sample size was determined based on the ability to detect a difference in the primary outcome variable, nausea. Previous studies have suggested that the incidence of postoperative nausea after surgery with a volatile anesthetic is about 70%. Because of the high likelihood of nausea, it is considered standard of care at our institution to prophylactically administer ondansetron, as we did in this study. With ondansetron prophylaxis, the incidence of nausea is still about 40%.14 With 25 patients in each group we had 80% power to detect a 30% difference in the incidence of nausea with 0.05 probability.
The data were analyzed according to an intention-to-treat method. Patient demographics, pupil size, and side effect data were compared using Student’s t-test for continuous variables and Fisher’s exact test for categorical variables (GraphPad InStat 3.06, San Diego, CA). Postoperative pain and pupil size were analyzed using repeated measures ANOVA with SPSS Graduate Pack version 14.0 (Chicago, IL).
Fifty patients were enrolled in the study. There were no significant demographic differences or differences in surgical procedures between the groups (Table 1). Although only five men were enrolled in this study, they were evenly distributed between the two groups. In the hydromorphone treatment group, one patient was unblinded after 1 h of treatment because of severe pain and at the request of the clinical team. The patient was switched to morphine PCA, which improved her symptoms, but was included in the hydromorphone group for the analysis because of the intention-to-treat design of the study.
There was no statistically significant difference in amount of postoperative pain reported at rest between the morphine and hydromorphone groups at 1 and 8 h after surgery (Fig. 1). There was also no difference in pain with movement after surgery between the 2 groups (1 h: morphine NRS = 7.9 ± 2.3, hydromorphone = 7.1 ± 2.4. 8 h: morphine NRS = 5.7 ± 2.8, hydromorphone: 5.9 ± 2.7). There was no difference between pupil size at baseline (4.2 ± 1.0 mm morphine and 4.2 ± 0.9 mm hydromorphone). The groups had the same degree of miosis after surgery and opioid treatment at 1 and 8 h (Fig. 2). The morphine group had pupillary constriction to 2.0 ± 0.4 mm 1 h after surgery and 2.3 ± 0.5 mm, 8 h after surgery. The hydromorphone group’s pupils were 2.0 ± 0.5 mm 1 h after surgery and 2.4 ± 0.7 mm 8 h after surgery.
One hour after surgery, patients used an average of 10.9 ± 6.0 mg of morphine or 1.57 ± 1.0 mg of hydromorphone via PCA (Table 2). The ratio of morphine to hydromorphone use on a milligram basis was 7.0:1.0. Eight hours after surgery, patients used an average of 29 ± 18 mg of morphine and 3.9 ± 2.5 mg of hydromorphone (P = 0.03) for a ratio of 7.4:1.0.
There were no statistically significant differences between the morphine and hydromorphone groups in sedation scores, incidence of emesis, nausea, or pruritus, or satisfaction scores at 1 and 8 h (Table 2). In a subgroup analysis of those patients who did experience nausea (48% at 1 h and 68% at 8 h), there was no difference in the severity score of nausea or the number of doses of antinausea medications required for treatment. In those patients with pruritis (10% at 1 h and 40% at 8 h), there was no difference in severity score and no patient required treatment (Table 2).
In this randomized, double-blind, placebo-controlled trial, we determined that in patients who titrated themselves to equivalent drug effect, as measured by reported analgesia and miosis, there was no difference in the incidence or severity of side effects between morphine and hydromorphone treatment. It should be kept in mind that this trial was designed to detect only a 30% difference in incidence of nausea, and thus smaller differences between the two drugs cannot be excluded with certainty.
One of the difficulties in comparing morphine and hydromorphone is that hydromorphone is a much more potent μ-opioid receptor agonist than morphine. In converting between the two opioids, an often quoted parenteral equianalgesic ratio from Goodman and Gilman 11th edition is 10 mg morphine to 1.5 mg hydromorphone.15 However, recent reviews of opioid conversions find ratios ranging from around 4:1 to as high as 8:1.11,16 Given this high degree of variability, we measured opioid-induced miosis to confirm that the μ agonist drug effect was equal in both groups before any comparison of side effects was undertaken. Morphine is thought to cause miosis by acting on μ receptors in the parasympathetic nervous system, possibly in the Edinger-Westphal nucleus.17,18 The pharmacodynamics of morphine-induced miosis in humans have been characterized by several studies,19–21 and degree of miosis has been used as a surrogate for blood level concentrations with opioids such as alfentanil.22,23 Morphine and hydromorphone did not exhibit differential selectivity in their effects on analgesia and miosis. Most studies, including ours, find that opioids reduce pupil size to a minimum of 2 mm. We had anticipated that the papillary response to the opioid would be graded. However, at the doses required for postoperative analgesia, papillary constriction was saturated. We conclude that patients treated with both drugs were titrating themselves to saturated papillary constriction.
There was no difference in incidence of vomiting, nausea, or pruritus between the two treatment groups. In a retrospective comparison of morphine and hydromorphone PCA, Hutchinson et al. also found no difference but they did not report relative amounts of opioids used.24 A prospective study by Rapp et al. that found that there was no difference in the incidence of nausea, vomiting, or pruritus in postoperative PCA users of morphine and hydromorphone, and this study reported a self-titrated analgesia at a ratio of 5:1.25 With the caveat that our study was not powered for a subgroup analysis, we found that of those patients experiencing nausea, there was no difference in the magnitude or number of doses of antinausea medications required for treatment. Morphine induces histamine release, but it is currently unclear how much of the pruritis caused by different opioids is due to histamine or due to a central μ agonist effect.15,26 We did not find any increase risk of pruritus induced by morphine.
Rapp et al. found that cognitive performance was poorer, whereas mood was improved, in the hydromorphone group.25 We did not find a difference in sedation or patient satisfaction that might be influenced by mood. Although our study did not find a difference in postoperative sedation, the Ramsey sedation score measurements are gross categories and lack the resolution of the more sophisticated cognitive and mood tests used by Rapp et al. Thus, our study does not address possible differences in cognitive or affective function between morphine and hydromorphone.
There were two additional limitations of our study. First, at our institution, it is standard practice to administer opioids as part of a balanced anesthetic. We only controlled postoperative PCA use and we did not match the opioids given during surgery with the treatments given afterwards. There was no statistical difference in either the type or amount of opioids given during surgery between the two treatment groups as a whole. Although small differences in side effects or efficacy might be masked by residual opioid given during surgery at 1 h, it would be highly unlikely that the effect would persist to the 8 h time point as at least 2 half-lives have passed for each drug used. A second limitation was the resolution of our time points. Hydromorphone has a faster onset of maximum analgesic effect (10–20 min) than morphine.6 It is possible that patients would have had higher satisfaction scores sooner with hydromorphone than with morphine had our measurements occurred at times before 1 h. However, we have excluded differences in gastrointestinal side effects. Patients have been known to cite postoperative nausea and vomiting as causing greater distress than even incisional pain when using opioids.27
Although there appear to be no population-based differences in the response to morphine or hydromorphone, there may be intraindividual differences to consider when treating patients. In patients who do experience severe pain or side effects with a given opioid, there are several studies that endorse improvement with opioid rotation.28–30 In our study, one patient experienced relief from refractory postoperative pain when switched from hydromorphone to morphine. Another patient experienced intense pruritus until he was successfully switched from hydromorphone to morphine, although this switch occurred after our 8 h observation period. Morphine and hydromorphone are both metabolized by UGT 1A3 and 2B7 as well as other hepatic enzymes.31 There are ethnically associated differences in morphine glucuronidation, presumably genetically mediated, that affect the incidence of respiratory depression.32 Future research may determine whether genetic polymorphisms in metabolism or variants of the μ receptor33 may predict idiosyncratic individual responses to different opioid medications.
1. Pick CG, Cheng J, Paul D, Pasternak GW. Genetic influences in opioid analgesic sensitivity in mice. Brain Res 1991;566:295–8
2. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer 2001;9:84–96
3. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985;62:124–9
4. Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release during morphine and fentanyl anesthesia. Anesthesiology 1982;56:93–6
5. Belov L, Meher-Homji V, Putaswamy V, Miller R. Western blot analysis of bile or intestinal fluid from patients with septic shock or systemic inflammatory response syndrome, using antibodies to TNF-α, IL-1α and IL-1β. Immunol Cell Biol 1999;77:34–40
6. Coda B, Tanaka A, Jacobson RC, Donaldson G, Chapman CR. Hydromorphone analgesia after intravenous bolus administration. Pain 1997;71:41–8
7. Chang AK, Bijur PE, Meyer RH, Kenny MK, Solorzano C, Gallagher EJ. Safety and efficacy of hydromorphone as an analgesic alternative to morphine in acute pain: a randomized clinical trial. Ann Emerg Med 2006;48:164–72
8. Mahler DL, Forrest WH Jr. Relative analgesic potencies of morphine and hydromorphone in postoperative pain. Anesthesiology 1975;42:602–7
9. Chaplan SR, Duncan SR, Brodsky JB, Brose WG. Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison. Anesthesiology 1992;77:1090–4
10. Halpern SH, Arellano R, Preston R, Carstoniu J, O’Leary G, Roger S, Sandler A. Epidural morphine vs hydromorphone in post-caesarean section patients. Can J Anaesth 1996;43:595–8
11. Patanwala AE, Duby J, Waters D, Erstad BL. Opioid conversions in acute care. Ann Pharmacother 2007;41:255–66
12. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev 2002:CD003447
13. Ramsay MAE ST, Simpson BRJ, Goodwin R. Controlled sedation with alfaxolone-alphadolone. BMJ 1974;2:656–9
14. Apfel CC, Stoecklein K, Lipfert P. PONV: a problem of inhalational anaesthesia? Best Pract Res Clin Anaesthesiol 2005;19: 485–500
15. Gutstein HBA, Huda. Opioid Analgesics. In: Brunton LL, ed. Goodman and Gilman’s the pharmacological basis of therapeutics. New York, NY: McGraw Hill, 2006
16. Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E. Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing. J Pain Symptom Manage 2001;22: 672–87
17. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–80
18. Lee HK, Wang SC. Mechanism of morphine-induced miosis in the dog. J Pharmacol Exp Ther 1975;192:415–31
19. Knaggs RD, Crighton IM, Cobby TF, Fletcher AJ, Hobbs GJ. The pupillary effects of intravenous morphine, codeine, and tramadol in volunteers. Anesth Analg 2004;99:108–12
20. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lotsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003;73:107–21
21. Dershwitz M, Di Biase PM, Rosow CE, Wilson RS, Sanderson PE, Joslyn AF. Ondansetron does not affect alfentanil-induced ventilatory depression or sedation. Anesthesiology 1992;77: 447–52
22. Kharasch ED, Walker A, Hoffer C, Sheffels P. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimally invasive and noninvasive probes for hepatic and first-pass CYP3A activity. J Clin Pharmacol 2005;45:1187–97
23. Kharasch ED, Hoffer C, Walker A, Sheffels P. Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity. Clin Pharmacol Ther 2003;73:199–208
24. Hutchinson RW CE, Tucker WF, Gilder R, Moss J, Daniel P. A Comparison of a fentanyl, morphine, and hydromorphone patient-controlled intravenous delivery for acute postoperative analgesia: a multicenter study of opioid-induced adverse reactions. Hospital Pharmacy 2006:659–63
25. Rapp SE, Egan KJ, Ross BK, Wild LM, Terman GW, Ching JM. A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia. Anesth Analg 1996;82: 1043–8
26. Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone hydrochloride. J Pain Symptom Manage 1999;17:70–2
27. Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg 1999;89:652–8
28. Ashby MA, Martin P, Jackson KA. Opioid substitution to reduce adverse effects in cancer pain management. Med J Aust 1999; 170:68–71
29. Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994;59:313–6
30. MacDonald N, Der L, Allan S, Champion P. Opioid hyperexcitability: the application of alternate opioid therapy. Pain 1993; 53:353–5
31. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part I. Psychosomatics 2003;44:167–71
32. Cepeda MS, Farrar JT, Roa JH, Boston R, Meng QC, Ruiz F, Carr DB, Strom BL. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2001;70:351–61
33. Schelling G, Hauer D, Azad SC, Schmoelz M, Chouker A, Schmidt M, Hornuss C, Rippberger M, Briegel J, Thiel M, Vogeser M. Effects of general anesthesia on anandamide blood levels in humans. Anesthesiology 2006;104:273–7 thase dependent. Stroke 2002;33:1889–98