Out of 1428 phone responders, 1362 had either back pain alone, pain location and quality that were typical of myofascial pain in the lower extremities (localized stiffness and dull aching pain in the buttock, thighs or legs), pain of lesser duration or intensity than required by the study, or were not interested in a drug treatment study. Sixty one of the sixty six respondents who qualified for the study based on the phone screening and were willing to participate in a drug trial met the inclusion and exclusion criteria.
Of 61 patients that underwent screening (), 6 declined to participate in the study prior to randomization to study medications. Nine patients dropped out during or after treatment with morphine alone. (Five withdrew because of side effects, 3 moved away and 1 withdrew for personal reasons); 3 dropped out during or after treatment with nortriptyline (2 withdrew because of side effects and 1 due to an unrelated medical problem); 6 patients dropped out during or after combination treatment (4 due to side effects and 2 for personal reasons); 9 dropped out during or after treatment with placebo (1 due to side effects, 3 because of lack of pain relief, 3 moved away, 1 due to an unrelated surgery, and 1 was excluded because of noncompliance). Examination of dropouts according to sequence shows that 9 patients dropped out of the morphine-placebo-nortriptyline-combination sequence; 7 patients dropped out of the placebo-combination-morphine-nortriptyline sequence; 4 patients dropped out of the combination-nortriptyline-placebo-morphine sequence; 6 dropped out of the nortriptyline-morphine-combination-placebo sequence. None of the patients who opted to participate in the study were on opioids during the two months prior to study entry.
Twenty-eight patients completed the trial (). One patient violated the protocol by taking opioids in addition to study medications during the second period of the study. He was therefore was excluded from the trial at that time and his scores were not included in the analysis There were no differences among the demographic and baseline characteristics of patients who underwent randomization, study completers and patients who completed at least two periods (). None of the patients were involved in litigation for compensation or disability for their pain at the time of screening and during the course of the study. None of the patients who participated in the study met critieria for multisomatoform disorder on the PHQ-15.
Mean doses were: nortriptyline alone, 84 +/− 24.44 (SD)mg/day; morphine alone, 62 +/−29mg/day; and combination, morphine, 49 +/−27 mg/day plus nortriptyline, 55 mg+/− 33.18 mg/day. None of the patients were taking quinidine, SSRIs or other significant inhibitors or inducers of cytochrome P450 2D6 isozymes, the key metabolizers of nortriptyline.
Effect of Treatments
There were no significant differences among the four treatments for average leg pain, the primary study outcome, either for patients who completed at least two treatments or for the 28 study completers. For the 28 study completers, percent reductions in average leg pain during the last two weeks of maintenance treatment were 7% for morphine (95% CI= [−8%, 22%]), 14% for nortriptyline (95% CI= [−2%, 30%]), and 7% for the combination treatment (95% CI= [−4%, 18%]) as compared to placebo for the 28 study completers(). Treatment effects on the other pain outcome scores for the 28 study completers were also not significant ().
Pain Scores in 28 Study Completers
Among patients who completed at least two periods, treatment was significant only in the model for worst overall pain (p=0.02). A Bonferroni procedure was used to adjust for the 6 comparisons made within each pair of drug treatments. Adjusted pairwise comparisons showed that only the combination treatment was significantly better than placebo (p=0.04). The analysis of the first period data only for average back pain showed that treatment was significant in the overall model (p=0.005). After adjusting p-values in a similar fashion for multiple testing, pairwise comparisons showed that nortriptyline was significantly better than placebo (p=0.01) and morphine alone (p=0.02).
The primary analysis for the 28 study completers showed no significant period or carry over effect between any two possible sequences of treatment. Among the 34 patients who completed at least two periods, there were no significant period or carryover effects between any two possible sequences of treatments for any of the pain scores except for average back pain where period effect was significant (p= 0.04).
The number of patients reporting moderate pain relief or better on the Global Pain Relief questionnaires for, morphine, nortriptyline, the combination treatment and placebo were 13 (42%), 12 (40%), 18 (67%), and 11 (37%) respectively. Wilcoxon Rank Tests were associated with p values of 0.46 for morphine, 1 for nortriptyline and <0.0001 for the combination treatment as compared to placebo respectively. P values for the comparison of morphine to nortriptyline (p=0.27), morphine to the combination treatment (p=0.061), and nortriptyline to the combination treatment (p=0.093) were not significant.
“Sequence” was not significant for any of the SF-36 outcome scores in the linear mixed models using scores for the patients who completed at least two periods. Significant period effect was found for the reported health transition category of the SF-36 (p=0.045); “treatment” in the modified model for this category where only data from the first period treatment was used did not reach statistical significance. In the analysis for the 28 study completers, there was a period effect (p=0.04) for one category of the SF-36, the role physical and for the category social function there was a carry over effect (p=0.02). Treatment in the modified models with the scores from the first treatment only was not significant for either category. For patients who completed at least two periods, “treatment” was not statistically significant in the linear mixed models fitted for either the Beck Depression Inventory (p=0.14) () or the Oswestry Disability Index (p= 0.2) (). For the 28 study completers treatment was not significant in the models fitted for the Beck Depression Inventory (p=0.15) and the Oswestry Disability Index (p=0.082) either.
Mean Scores on the Beck Depression Inventory (BDI) and the Oswestry Disability Index (ODI):
Analysis in all patients with analyzable data for the SF-36 health survey () showed that treatment was not associated with statistical significance for any of the categories except for: (1) The “Emotional Role” subscale (overall model’s p = 0.04), for which after adjusting the p value with a Bonferroni procedure only the combination treatment was associated with higher scores compared to placebo (p=0.03); And (2)The “Mental Health” subscale, for which treatment was significant at 0.04 in the overall model but the adjusted p values for pairwise comparisons using the Bonferroni procedure did not reach statistical significance.
By chance alone, an observer would identify each of four treatments correctly an average of 25% of the time. On the blinding questionnaires, the numbers of correct guesses by patients were 9 (32%) for morphine treatment periods, 9 (32%) for nortriptyline, 10 (37%) for the combination treatment, and 11 (39%) for placebo. The frequencies of nurses’ correct guesses were 7 (35%) for morphine, 5 (17%) for nortriptyline, 4 (25%) for the combination treatment, and 9 (50%) for placebo. A percent larger than 25% for any treatment suggests that the patients or nurses were not optimally blinded during that treatment.
Adverse effects and NNH
At the maximal tolerated doses, the most frequent adverse effects reported by the study completers were constipation, dry mouth, drowsiness, and fatigue (Table 7). During the morphine treatment two patients withdrew because of sedation, one because of nausea, vomiting and severe constipation, one because of a rash, and severe dry mouth, while during the nortriptyline treatment two withdrew because of sedation. During the combination treatment two patients withdrew because of sedation, one because of nausea and vomiting, and one because of a rash whereas during the placebo treatment one patient withdrew because of sedation. NNHs were 10, 30, and 11 for morphine, nortriptyline and the combination treatment respectively.