The Side Effects of Morphine and Hydromorphone Patient-Controlled Analgesia

Abstract

BACKGROUND: 

Despite “clinical lore” among health care providers that treatment with hydromorphone results in improved pain control and fewer adverse side effects, morphine continues to be the first-line medication for postoperative patient-controlled analgesia (PCA). In this study, we compared the efficacy and side-effect profiles of morphine and hydromorphone at concentrations producing equivalent drug effect measured by pain score and miosis.

METHODS: 

We conducted a prospective, randomized, double-blind trial of 50 general and gynecological surgery patients. Subjects were randomly assigned to receive either morphine (1 mg/mL) or hydromorphone (0.2 mg/mL) via PCA after surgery and were followed for a period of 8 h. The primary outcome was nausea. Secondary outcome variables were pruritus, vomiting, sedation, pain report, pupillary miosis, and patient satisfaction.

RESULTS: 

The side effect profile was not different between drugs. The incidence of nausea did not differ between morphine and hydromorphone-treated patients (1 h: 44% vs 52%, 8 h: 68% vs 64%), vomiting (1 h: 4% vs 0%, 8 h: 0% vs 4%), or pruritus (1 h: 4% vs 16%, 8 h: 40% vs 40%). There was no difference in the amount of medication required to treat side effects or patient satisfaction.

The average ratio of morphine to hydromorphone use was about 7:1. The patients used 10.9 ± 6.0 mg morphine versus 1.57 ± 1.0 mg hydromorphone after 1 h and 29.0 ± 18.0 mg morphine versus 3.9 ± 2.5 mg hydromorphone after 8 h. There was no difference between the morphine and hydromorphone groups with respect to postoperative pain scores with movement at 1 h (7.9 ± 2.3 vs 7.1 ± 2.4) or 8 h (5.7 ± 2.8 vs 5.9 ± 2.7). There was also no difference in pain at rest or miosis between groups.

CONCLUSIONS: 

We found no systematic difference between morphine and hydromorphone in opioid-related side effects. Neither was there any difference in efficacy of pain control or patient satisfaction when patients self-titrated to equal drug effect as measured by equianalgesia and pupillary miosis. The choice between morphine and hydromorphone for use in PCA should be guided by patient history, as there may be idiosyncratic reactions to either drug.

In Brief

IMPLICATIONS: In a randomized, double-blind trial of 50 patients, we found no difference in nausea, vomiting, pruritus, or sedation between morphine and hydromorphone groups treated with patient controlled analgesia. There was evidence for an equianalgesic effect as measured by patient pain report and pupillary constriction.

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 pain^5,6 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.

METHODS

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.

Study Design

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.

Statistical Analysis

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).

RESULTS

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.

Table 1: Demographic and Surgical Characteristics of Patients

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.

Figure 1.: Postoperative pain. There was no difference in the postoperative pain reported over 8 h between the (A) morphine and (B) hydromorphone patient-controlled analgesia groups. Pain was measured on a numerical rating scale from 0 to 10. Gray lines represent each individual patient and black lines and error bars represent the mean and sd. n = 25 for both groups.

Figure 2.: Opioid-induced miosis after surgery. There was no difference in the postoperative miosis induced by (A) morphine and (B) hydromorphone over 8 h. Pupil diameters are the averages of the left and right eyes. Gray lines represent individual patients and black lines and error bars represent the mean and sd. n = 25 for both groups.

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.

Table 2: Side Effect Profile of Morphine and Hydromorphone Patient-Controlled Analgesia

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).

DISCUSSION

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.