Intrathecal morphine sulfate (ITMS) was shown by Wang et al. (1) in 1979 to provide profound and prolonged analgesia and is now used extensively to treat acute postoperative and cancer-related pain. The analgesia produced by ITMS is adequate for pain relief after many different types of surgery in doses ranging from 0.025 to 20 mg (2–4). A single dose often suffices as the sole analgesic after surgery, including major orthopedic surgery (4–7). However, doses in excess of 0.5–1 mg are associated with a marked increase in side effects, including significant respiratory depression (5,8).
Pain after hip and knee arthroplasty can be effectively controlled with ITMS (7,8,9). However, postoperative analgesia with ITMS is associated with dose-related side effects, including nausea and vomiting (N/V), pruritus, urinary retention, and respiratory depression (10). In an attempt to limit side effects, the use of small-dose spinal opioids (e.g., <0.3 mg of ITMS) has been advocated (8,11,12). Prior studies examining the use of ITMS after total joint arthroplasty have failed to determine an optimal dose for patients undergoing knee replacement (8,9). Earlier studies (8) have also been hampered by combining hip and knee arthroplasties in their analyses. Salmon et al. (13) demonstrated that there is significantly more postoperative pain after knee arthroplasty than after hip arthroplasty and pointed out that the practice of combining the two in the evaluation of outcomes is invalid. This series stratified patients undergoing hip and knee arthroplasty in a prospective, randomized, double-blinded, placebo-controlled dose-ranging study designed to examine side effects, pain relief, and the need for supplemental analgesics with ITMS after each type of surgery.
After IRB approval, written, informed consent was obtained from adults undergoing primary total knee or hip replacement. Patients were excluded from the study if they refused spinal anesthesia, had significant preoperative opioid analgesic use (>30 mg/d of oral morphine or the equivalent), were scheduled for multiple joint or revision surgery, had laboratory evidence of coagulopathy (platelet count <100,000/mm3, prothrombin time >13.1 min [international normalized ratio >1.2], and partial thromboplastin time >33 min), or had significant pulmonary disease (reactive airway disease or chronic obstructive pulmonary disease requiring daily bronchodilator or steroid use and/or room air oxygen saturation <95% immediately before surgery).
Patients were first stratified into two groups: those undergoing total hip replacement and those undergoing total knee replacement. Patients were then randomized to one of four treatment groups by dose: 0.0 (control), 0.1, 0.2, or 0.3 mg of ITMS. All patients underwent spinal anesthesia, performed by an anesthesiologist not involved with the subsequent data collection, by using tetracaine with epinephrine mixed with the assigned ITMS dose (diluted to 0.3 mL with preservative-free saline). All patients received hyperbaric tetracaine (1% tetracaine solution mixed 1:1 with 10% dextrose solution) with 0.2 mg of epinephrine (0.2 mL of 1:1000 epinephrine solution). The dose of tetracaine and the remainder of the intraoperative anesthetic care was left to the discretion of the anesthesiologist caring for each patient.
Patients were observed in the postanesthesia care unit (PACU) until regression of their sensory level below the T12 dermatome (hip arthroplasty) or the L3 dermatome (knee arthroplasty). IV morphine was administered in the PACU by a nurse blinded to the treatment group until the patient reported a verbal analog scale score of <4 (0–10 scale). Thereafter, all patients received IV morphine via a patient-controlled analgesia (PCA) device (Ipump; Baxter Healthcare Corp., Round Lake, IL) for the first 24 h postoperatively (no basal infusion, 1-mg dose, 10-min lockout, 6 mg/h limit). If pain relief was inadequate at any time after the patient left the PACU, an additional bolus dose of 2 mg of IV morphine was given, and the PCA was adjusted to allow 1.5 mg per dose. No patient in the study required adjustment of the PCA beyond this.
Sedation, side effects, and pulse oximetry were assessed and recorded every 2 h on the orthopedic ward. Supplemental oxygen was not placed routinely; however, whenever evaluation revealed oxygen saturation <93%, oxygen 3 L/min via nasal cannula was added. There were no observations of oxygen saturation <93% in any patient once supplemental oxygen had been placed. All personnel collecting data remained blinded to the treatment groups. A blinded investigator visited each patient 24 h after the surgery to assess overall satisfaction and download the electronic record of IV morphine use directly from the PCA device.
The primary outcome measure was total IV morphine use for the first 24 h after surgery. Secondary outcome measures included patient satisfaction, N/V, pruritus, and O2 saturation <93%. Patient satisfaction was rated during the 24-h postoperative visit on the basis of their subjective perception of overall pain relief (0 = no pain relief; 1 = poor pain relief; 2 = good pain relief; 3 = excellent pain relief). The incidence and severity of pruritus and N/V were assessed with a scale previously reported by Palmer et al. (5) (0 = none; 1 = mild, no treatment requested by patient; 2 = moderate to severe, treatment requested by patient).
A power analysis based on a previous dose-response study of ITMS (5) indicated that 10 patients per treatment group would allow detection of a 30% reduction in 24-h IV PCA morphine use (1 − β = 0.8; α = 0.05). Quantitative demographic data (age, height, and weight) and IV morphine consumption were analyzed with analysis of variance to detect significant differences among the 4 treatment groups (0.0, 0.1, 0.2, and 0.3 mg). Pairwise comparisons of the treatment groups were performed at 0 h (defined as the time of discharge from the PACU), 12 h, and 24 h and were corrected for multiple comparisons by using a Bonferroni correction. The three time points were chosen prospectively as clinically meaningful time points; pairwise comparisons were performed at only three time points to improve the overall power of the final analysis. Discrete variables (sex, side effects, and satisfaction scores) were analyzed with χ2 testing. Potential confounding by baseline variables (dose, age, sex, height, and weight) was analyzed with linear regression (analysis of covariance). All data are given as mean ± sd; statistical significance was considered at P < 0.05.
Eighty patients were enrolled (40 patients undergoing hip arthroplasty and 40 patients undergoing knee arthroplasty); 10 patients were randomized to each treatment group. Two patients were excluded from analysis because of protocol violations. One patient who underwent knee arthroplasty was randomized to the 0.3 mg group but had a history of preoperative opioid use (extended-release morphine 90 mg 3 times daily) that was not reported before surgery. The second excluded patient underwent hip arthroplasty and was randomized to the 0.3 mg group. After surgery, the surgical service discontinued the PCA and administered meperidine at the patient’s request.
There were no significant differences in demographics or doses of spinal tetracaine among treatment groups except when age and sex were compared (Table 1). Hip arthroplasty patients were significantly older in the 0.2 mg group when compared with the other treatment groups. Of knee arthroplasty patients, the group receiving 0.3 mg had significantly more women than the control and 0.2 mg groups.
After hip arthroplasty, postoperative PCA morphine use was significantly less in patients receiving ITMS than in the control group (Fig. 1). Pairwise comparisons of PCA morphine requirements were made at discharge from the PACU (0 h) and at 12 and 24 h after discharge from the PACU (Table 2). Morphine requirements during the stay in the PACU were significantly smaller in the 0.2 and 0.3 mg groups than in the control group. PCA morphine requirements were significantly smaller in patients who received 0.1, 0.2, or 0.3 mg of ITMS than in the control group at both 12 and 24 h after discharge from the PACU, but there were no differences among any of the treatment groups that received ITMS. Hip arthroplasty patients who received 0.2 or 0.3 mg of ITMS were more satisfied with their overall pain control than those receiving 0.0 or 0.1 mg (Table 3).
After knee arthroplasty, none of the three doses of ITMS reduced postoperative PCA morphine use (Fig. 2). Again, pairwise comparisons of PCA morphine use were made at discharge from the PACU (0 h) and at 12 and 24 h after discharge from the PACU (Table 2). PCA morphine requirements at discharge from the PACU (0 h) and at 12 h were not significantly different. At 24 h, the groups receiving 0.1 and 0.3 mg of ITMS had received significantly more PCA morphine than the control group. Overall satisfaction with pain control was significantly higher in the knee arthroplasty groups receiving 0.2 and 0.3 mg of ITMS than in the control group (Table 4).
The incidence of side effects differed significantly among treatment groups. Of the patients undergoing hip arthroplasty (Table 3), only those in the 0.3 mg group had significantly more frequent N/V than the control group; all other treatment groups were similar. All hip arthroplasty patients who received ITMS had significantly more pruritus that required treatment than the control group. There were no significant differences in the incidence of recorded oxygen saturation <93% among treatment groups.
Of the patients undergoing knee arthroplasty, there were no significant differences in the incidences of N/V requiring treatment or the number of patients with pulse oximeter readings <93% among treatment groups (Table 4). Knee arthroplasty patients receiving ITMS had significantly more pruritus requiring treatment than the control group.
This study demonstrates that small-dose ITMS (0.1–0.3 mg) provides good analgesia and significantly reduces the need for additional IV morphine during the first 24 hours after total hip arthroplasty. The same doses of ITMS in combination with IV morphine via PCA provide good analgesia but do not reduce the need for supplemental IV morphine after total knee arthroplasty; indeed, patients receiving ITMS required more supplemental IV morphine during the first 24 hours after surgery than those who received no ITMS. Although patients receiving ITMS experienced more frequent opioid-related side effects (pruritus and N/V), their overall pain relief was superior after both hip and knee arthroplasty.
ITMS is effective for acute postoperative pain control in patients undergoing a number of different types of surgery (4–7). However, the reliability of small-dose ITMS was questioned by Jacobson et al. (8), who found that 0.3 mg was not as effective in providing postoperative analgesia as either 1 or 2.5 mg in patients undergoing total joint arthroplasty. Although the larger doses produced improved pain relief, they were associated with severe respiratory depression in some patients. Kalso (7) also found that a dose of 0.2 mg of ITMS did not adequately relieve postoperative pain during the first 10 hours after joint-replacement surgery. Both of these studies examined patients undergoing either hip or knee replacement and assumed that the amount of pain and the recovery from the two procedures was similar. In a prospective analysis of patients recovering from hip and knee arthroplasty, Salmon et al. (13) found that patients who underwent knee replacement reported significantly more pain than those who had hip replacement. Thus, the practice of combining them in the evaluation of outcome is not valid. In this study, we demonstrated that the need for supplemental IV morphine for pain control after hip arthroplasty was significantly reduced by the use of small-dose ITMS (0.1 – 0.3 mg). However, the need for supplemental IV morphine for pain control after knee arthroplasty was not reduced by similar doses of ITMS. This suggests that pain after knee arthroplasty was more intense than that after hip arthroplasty in our study population, thus resulting in an increased need for supplemental analgesics after knee arthroplasty. The conclusion of earlier investigators that small-dose ITMS does not provide adequate analgesia after total joint replacement may be, in part, due to combining two surgical procedures with disparate analgesic needs.
Surprisingly, the amount of supplemental IV morphine required after knee arthroplasty in patients receiving either 0.1 or 0.3 mg was actually larger than the amount required by patients in the control group. There is no clear explanation for this finding. However, while in the PACU and for the first eight hours after discharge, patients receiving ITMS appeared to need less supplemental IV morphine than the control group (this was not statistically significant at the time of discharge from the PACU). We hypothesize that the analgesia provided by ITMS was adequate for only approximately eight hours after surgery (see Fig. 2, which shows that PCA morphine use increased dramatically after eight hours in the 0.3 mg treatment group). Because patients who had received ITMS initially needed less systemic morphine, as the effects of the ITMS waned and pain increased, they may have required more supplemental morphine than the control patients to attain adequate analgesia (i.e., they needed an initial loading dose to establish an adequate serum concentration of morphine).
Despite markedly different patterns of IV PCA morphine use after hip and knee arthroplasty, more patients reported “good” or “excellent” pain relief after receiving the larger doses of ITMS tested (0.2 and 0.3 mg) after both types of surgery. Thus, there is a disparity between supplemental analgesic use (IV PCA use) and patient report of pain relief. Indeed, 4 (40%) of 10 and 5 (50%) of 10 patients after hip and knee arthroplasty, respectively, reported “no pain relief” or “poor pain relief” when they had received no ITMS (control groups). In contrast, only 1 (5%) of 19 and 2 (11%) of 19 patients after hip and knee arthroplasty, respectively, who had received 0.2 or 0.3 mg of ITMS reported “no pain relief” or “poor pain relief.” Although small-dose ITMS did not reduce the need for supplemental analgesics after knee arthroplasty, it appears to have improved the analgesia over IV morphine alone.
ITMS was associated with minor side effects at all of the doses tested. Patients receiving ITMS, regardless of the joint replaced, had significantly more pruritus requiring treatment than the control group. The group of patients undergoing hip arthroplasty with 0.3 mg of ITMS had significantly more N/V than the control group. None of the other groups receiving ITMS showed any difference in N/V when compared with the control group, regardless of the joint replaced. This is consistent with previous publications that have shown increased pruritus, but no increase in N/V, in patients receiving ITMS (5). There were no significant differences among the groups of patients receiving ITMS versus the control group with respect to hypoxemia during the first 24 hours after surgery, and there were no episodes of respiratory depression requiring treatment, even in elderly patients who received 0.3 mg of ITMS and went on to receive significant doses of PCA morphine. This is consistent with the work of previous investigators who reported only mild hypoxemia in a fraction of patients who received small-dose ITMS (5,8,9). Although urinary retention is common after the administration of ITMS, all patients in this study had an indwelling urinary catheter placed before surgery.
This study has several limitations. Despite randomization, there were significant demographic differences: there was an older average age in the groups receiving 0.2 and 0.3 mg of ITMS who underwent hip arthroplasty, and there were significantly more female patients in the group receiving 0.3 mg of ITMS who underwent knee arthroplasty than other treatment groups. The effect of these uneven allocations on our results is unclear. We measured oxygen saturation levels only intermittently (every two hours); thus, significant hypoxemia between observations cannot be excluded. However, there were no episodes of respiratory depression that required treatment other than the application of supplemental oxygen via nasal cannula. Finally, there are many alternative techniques for controlling pain after knee arthroplasty. Continuous nerve block techniques or epidural analgesia may well provide better postoperative analgesia, with fewer associated side effects, after total knee arthroplasty (14–17). Our work provides little information about the comparative usefulness of these different techniques.
In conclusion, this study demonstrates that small-dose ITMS coupled with standard doses of IV morphine via PCA provides good pain relief after either total hip or total knee arthroplasty. The addition of ITMS reduces the doses of supplemental IV analgesics required for pain control after hip replacement, but not after knee replacement, suggesting that the degree of pain and the analgesic requirements are greater after knee arthroplasty. Patients receiving IV morphine alone or combined with ITMS frequently experience N/V that requires treatment. ITMS results in more pruritus than IV PCA morphine alone. The optimal dose of ITMS for pain control after total hip arthroplasty appears to be 0.2 mg, a dose in which side effects are minimized and the analgesic effect is maximized. Combining small-dose ITMS with standard doses of supplemental morphine administered via PCA provides good to excellent pain control in most patients after total hip or knee arthroplasty.
1. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–51.
2. Samii K, Chauvin M, Viars P. Postoperative spinal analgesia with morphine. Br J Anaesth 1981; 53: 817–20.
3. Moore RA, Paterson GMC, Bullingham RES, et al. Controlled comparison of intrathecal cinchocaine with intrathecal cinchocaine and morphine: clinical effects and plasma morphine concentrations. Br J Anaesth 1984; 56: 837–41.
4. Davis I. Intrathecal morphine in aortic aneurysm surgery. Anaesthesia 1987; 42: 491–7.
5. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999; 90: 437–44.
6. Bengtsson M, Löfström JB, Merits H. Postoperative pain relief with intrathecal morphine after major hip surgery. Reg Anesth 1983; 8: 140–3.
7. Kalso E. Effects of ITMS, injected with bupivacaine, on pain after orthopaedic surgery. Br J Anaesth 1983; 55: 415–21.
8. Jacobson L, Chabal C, Brody MC. A dose-response study of intrathecal morphine: efficacy, duration, optimal dose and side effects. Anesth Analg 1988; 67: 1082–8.
9. Cole PJ, Craske DA, Wheatley RG. Efficacy and respiratory effects of low-dose spinal morphine for postoperative analgesia following knee arthroplasty. Br J Anaesth 2000; 85: 233–7.
10. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61: 276–310.
11. Sarma VJ, Bostrom UV. Intrathecal morphine for the relief of post hysterectomy pain: a double blind dose response study. Acta Anaesthesiol Scand 1993; 37: 223–7.
12. Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response pharmacology of intrathecal morphine in human volunteers. Anesthesiology 1993; 79: 49–59.
13. Salmon P, Hall GM, Peerbhoy D, et al. Recovery from hip and knee arthroplasty: patients’ perspective on pain, function, quality of life and well-being up to 6 months postoperatively. Arch Phys Med Rehabil 2001; 82: 360–6.
14. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral blocks improve recovery and outcome of patients undergoing total knee arthroplasty. J Arthroplasty 2001; 16: 436–45.
15. Singelyn FJ, Deyaert M, Joris D, et al. Effects of intravenous patient controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one-block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 1998; 87: 88–92.
16. Ganapathy S, Wasserman RA, Watson JT, et al. Modified continuous femoral three-in-one block for postoperative pain after total knee arthroplasty. Anesth Analg 1999; 89: 1197–202.
© 2003 International Anesthesia Research Society
17. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999; 91: 8–15.