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Departments of *Anesthesia and Perioperative Care and Neurology, University of California, San Francisco
Address correspondence and reprint requests to Pamela Pierce Palmer, MD, PhD, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 513 Parnassus Ave., Box 0464, Room S-455, San Francisco, CA 94143. Address e-mail to palmerp{at}anesthesia.ucsf.edu.
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Abstract |
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50 yr; 49 ± 3 mg/d oral morphine-equivalent dose) versus older patients (
60 yr; 42 ± 3 mg/d). Younger patients reached a maximum dose of 452 ± 63 mg/d over 15.0 ± 1.3 mo, whereas older patients achieved a maximum dose of 211 ± 23 mg/d over 14.4 ± 1.5 mo (P < 0.0001). At the last clinic visit, younger-patient dosing averaged 365 ± 61 mg/d, with older patients averaging 168 ± 18 mg/d (P < 0.0001). Only older patients demonstrated a reduction in visual analog scale scores from start of opioid therapy until discharge from the clinic (6.9 ± 0.3 to 5.6 ± 0.3; P < 0.01). These clinical data suggest that age is an important variable in opioid dose escalation. Although factors other than opioid tolerance can result in dose escalation, it is possible that older patients may have a reduced rate of tolerance development. |
Introduction |
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Opioid escalation can occur for a variety of reasons, including underlying disease progression, opioid addiction, and tolerance development. We have diagnostic tools to help identify disease progression, and there are guidelines in the literature to identify and manage pain patients who might be drug seeking or have a history of substance abuse (9,10). However, there are no guidelines to identify patients who may be poor candidates for long-term opioid treatment because of rapid opioid tolerance development and unsustainable long-term pain relief.
Whereas there are numerous reports studying the effects of age on pharmacokinetic variables of opioids, clinical pharmacodynamic tolerance to long-term daily opioids has never been studied in an age-dependent manner. Most clinical studies analyze patients from 18–80 yr as a single group, with the mean age usually in the 50- to 60-yr range. A study published in 1975 (11) suggested that the development of tolerance to daily morphine administration occurs more rapidly in young rats; however, the oldest rats used in this study were 12 wk. We completed a study of daily morphine administration in rats ranging in age from 3 wk to 1 yr (12). We found a dramatic prolongation in the time to onset of tolerance as the rats aged. These findings prompted us to perform a retrospective study of our pain clinic patients to determine whether opioid dose escalation was significantly different based on the age of the patient, as well as other factors, such as type of pain. Also we were interested in determining whether treatment with chronic long-acting opioids resulted in a significant reduction in pain scores over time.
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Methods |
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Oral morphine equivalent doses were compared using the nonparametric Mann-Whitney U-test and are reported as mean ± se of the mean (sem), and also the median is reported. The VAS scores were analyzed using the repeated-measures analysis of variance with Bonferroni post hoc test.
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Results |
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Daily oral morphine-equivalent dose at initiation, peak opioid dose, and opioid dose at time of discharge from the clinic are graphed for both the younger and older groups in Figure 1. There was no significant difference in initial opioid dosing between younger (49 ± 3 mg/d; median, 37 mg/d) and older (42 ± 3 mg/d; median, 30 mg/d) age groups. Both age groups increased opioid dosing over the same time period (peak opioid dose reached at 15.0 ± 1.3 mo in the younger group versus 14.4 ± 1.5 mo in the older group). However, the average peak opioid dose achieved in the younger group (452 ± 63 mg/d; median, 301 mg/d) was more than two-fold the maximum average dose achieved in the older group (211 ± 23 mg/d; median, 150 mg/d; P < 0.0001). Therefore, the younger group escalated on average 27 mg of daily oral morphine equivalent per month during the 15-mo period, whereas the older group escalated at a substantially slower rate of 12 mg of daily oral morphine equivalent per month. The total time on long-acting opioids (at last clinic appointment) for both age groups was similar and averaged 26.5 ± 1.6 mo in the younger group and 27.5 ± 2.1 mo in the older group. The final opioid dose was 20% smaller than the peak dose in both age groups, reflecting a halt and slight reversal of the dose escalation seen in the initial time period, which probably reflects physician-imposed prescribing limits or opioid-induced side effects. Final opioid dosing at time of discharge from the clinic remained significantly different among the age groups (younger, 365 ± 61 mg/d; median, 221 mg/d; older, 168 ± 18 mg/d; median, 101 mg/d; P < 0.0001).
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There were no differences in opioid dosing based on sex in either age group at initiation of long-acting opioid therapy, peak opioid dosing, or final opioid dosing (data not shown).
Within each group, a similar analysis was performed taking into account the patient’s type of pain: nociceptive versus neuropathic (Fig. 2, A and B). In the older patient population, no difference in opioid dosing was apparent based on type of pain (Fig. 2A). The older nociceptive pain group initiated long-acting opioid therapy at an average dose of 35 ± 4 mg/d (median, 30 mg/d) of oral morphine equivalent and increased to an average peak of 238 ± 40 mg/d (median, 175 mg/d) over 18.1 ± 3.3 mo. The older neuropathic pain group initiated long-acting opioid therapy at an average dose of 46 ± 4 mg/d (median, 37 mg/d) of oral morphine equivalent and increased to an average peak of 198 ± 28 mg/d (median, 150 mg/d) over 12.6 ± 1.6 mo. Therefore, the older nociceptive group averaged 11 mg daily of oral morphine equivalent per month escalation, whereas the older neuropathic pain group averaged 12 mg daily of oral morphine equivalent per month escalation. The final dose in the older nociceptive group averaged 200 ± 38 mg/d (median, 90 mg/d) after 29.4 ± 3.7 mo on long-acting opioids and was not significantly different from the final dose in the older neuropathic group, which averaged 153 ± 18 mg/d (median, 102 mg/d) after 26.6 ± 2.6 mo on long-acting opioids.
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However, in the younger patients, whereas the opioid dose was similar at initiation of therapy (nociceptive, 55.1 ± 5.3 mg/d [median, 37 mg/d]; neuropathic, 42.4 ± 4.3 mg/d [median, 35 mg/d]), the dose escalation was significantly less (16 mg daily of oral morphine equivalent per month) in the neuropathic group (maximum dose, 317.9 ± 36.8 mg/d [median, 244 mg/day] over 17.2 ± 2.3 mo) than the nociceptive group (38 mg daily of oral morphine equivalent per month) (maximum dose, 562.9 ± 108.9 mg/d [median, 369 mg/d] over 13.2 ± 1.3 mo; P = 0.013) (Fig. 2B). The maximum dose in the younger neuropathic group (317.9 mg/d) was still significantly larger than the older group’s maximum dose of 210.8 mg/d (P = 0.002). The final dose in the younger nociceptive group averaged 449.4 ± 106.3 mg/d (median, 270 mg/d) after 25.2 ± 2.1 mo on long-acting opioids, whereas the final dose in the younger neuropathic group averaged 263.5 ± 36.9 mg/d (median, 175 mg/d) after 28.2 ± 2.4 mo on long-acting opioids (P = 0.06).
VAS scores were averaged for each age group upon first clinic appointment, before the first dose of long-acting opioid therapy, and at the time of discharge from the clinic on long-acting opioids (Fig. 3, A and B). Both age groups had a significant reduction in their VAS scores from first clinic appointment up until starting long-acting opioid therapy (younger, 8.4 ± 0.2 versus 6.2 ± 0.3; P < 0.0001; older, 8.3 ± 0.2 versus 6.9 ± 0.3; P < 0.01). The younger group averaged 3.9 ± 0.6 mo from the first clinic appointment until starting long-acting opioids, whereas the older group averaged 6.87 ± 1.1 mo.
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Important to note is that the younger group did not have a change in VAS scores measured from start of long-acting opioid therapy until time of discharge from the clinic (6.2 ± 0.3 versus 6.1 ± 0.3), although there was a 640% (49.3 mg/d to 365.4 mg/d) increase in daily opioid dose from the initiation of long-acting opioids until discharge on opioids—a period of 26.4 mo. In the older group, once long-acting opioid therapy was initiated, VAS scores further decreased from 6.9 ± 0.3 to 5.6 ± 0.3 (P < 0.01).
There were no differences in VAS scores depending on type of pain within each age group at any time point (from the first appointment, before starting the long-acting opioid, to discharge from the clinic. There were no differences in VAS scores based on sex in either age group.
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Discussion |
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In agreement with this finding is the study by Moulin et al. (17) who studied 46 chronic pain patients with nonneuropathic pain taking sustained-relief oral morphine up to 60 mg twice a day. This is one of the few published chronic pain studies in which the patients averaged only 40 years of age; therefore, this group is almost identical to our younger nonneuropathic group. Once the three-week dose-escalation phase was completed, patients during the 6-week evaluation on stable morphine dosing reported an almost complete loss of pain relief. Patients showed no functional improvement on opioid therapy in this study.
It is noteworthy that we did not include functional outcome measures in our study because there was not a consistent objective reporting of functional variables in the records. It could be argued that although no change was observed in VAS scores, the younger patients may have been more functional on the large-dose opioids. However, studies assessing VAS scores and functional outcome measures with opioid therapy for chronic nonmalignant pain have shown that increased functional outcomes are correlated with a decrease in VAS scores (6,18). Furthermore, the older patients in our study demonstrated long-term analgesic efficacy with opioids, based on VAS assessment, with less than half the dose escalation. Therefore, it is more likely that the younger patients experienced more rapid tolerance development resulting in no change in VAS scores rather than assuming an age-biased effect on pain reporting that is not substantiated in the literature.
It is unlikely that a difference in the rate of disease progression between the two age groups accounts for the differences in opioid escalation. Both age groups had a similar duration of chronic pain (more than eight years; Table 1) before entrance into the clinic, and patients with cancer pain were excluded from the study. Although age group entrance characteristics were similar between the two groups (Table 1), there was a larger ratio of neuropathic pain patients in the older study population compared with the younger group (Table 1). Because type of pain did not have an effect on rate of opioid escalation or VAS scores in the older population, this discrepancy does not seem to have altered the outcomes of this study.
The slower rate of opioid escalation observed in younger patients with neuropathic pain compared with younger patients with nociceptive pain may have been due to multiple factors. There are published animal data that support the concept of slower opioid tolerance development in neuropathic pain states compared with nociceptive inflammatory pain conditions (19,20), although no clinical studies have definitively substantiated this finding. It may also be the case that although opioids have proven efficacy in neuropathic pain conditions (21), more emphasis is placed on the aggressive use of adjuvant analgesics, such as anticonvulsants and tricyclic antidepressants, and therefore, opioid escalation is not aggressively pursued by either physician or patient. Yet, another factor may be the patient’s perception that their neuropathic pain is not effectively managed with opioids, and therefore, the lack of escalation is more because of a lack of perceived benefit by patient or physician. Finally, regardless of the type of pain, we cannot exclude the effect of pharmacokinetic differences between the two age groups.
If rapid tolerance to daily opioids occurs in younger chronic pain patients, is there a rationale for simply continuing to increase the opioid dose? Even with rapid tolerance development, a decrease in the younger group’s VAS scores may have been observed if we had continued opioid escalation throughout the entire two-year period of opioid therapy in our clinic. Studies reporting favorable analgesic data in long-term treatment of nonmalignant pain with opioid therapy have some patients escalating to half a gram per day of oral morphine equivalent or larger (conversion from intrathecal dose) (6–8). Long-term consequences of large-dose opioid therapy are receiving more attention lately (22), and with these concerns, the rationale for rapid chronic opioid escalation in nonmalignant pain comes into question.
The efficacy of chronic opioid therapy in the older group is an important finding of this study. The initial benefits of the multi-disciplinary pain management approach were enhanced by the addition of chronic long-acting opioid therapy. Long-term stable dosing was observed over two years accompanied by a significant reduction in VAS scores. The molecular changes that occur in neurons with aging are an important area of research that may provide novel insights into molecular mechanisms of opioid tolerance development.
The retrospective nature of this study is an obvious limitation, and a follow-up prospective study would be optimal. We can only suggest exercising caution when considering chronic daily opioids in younger patients with nonmalignant pain, especially for nonneuropathic pain conditions. Although opioid rotation is an option in cancer pain (23), it is unclear how effective or feasible opioid rotation is over decades of treatment. In some younger patients, focusing on the use of non-opiate therapies, along with intermittent use of opioids for severe breakthrough pain, has provided effective long-term pain management (anecdotal clinical observations). The use of opioids for acute exacerbation of chronic pain in younger patients can minimize their anxiety regarding these episodes as well as reduce their visits to the emergency room. Ultimately, more attention needs to be focused on the development of effective analgesics with minimal tolerance development.
In summary, age seems to be an important factor in determining which patients will require escalating doses of chronic daily opioids over time. Patients younger than 50 years escalated oral opioids at more than twice the rate of patients older than 60 years during the first year of opioid therapy. Although both age groups reported decreased pain scores after enrolling in our pain management center, only the older patients reported an additional decrease in pain scores two years after starting chronic daily long-acting opioid therapy.
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Footnotes |
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Accepted for publication November 16, 2004.
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This article has been cited by other articles:
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  N. Katz Methodological issues in clinical trials of opioids for chronic pain Neurology, December 29, 2005; 65(12_suppl_4): S32 - S49. [Abstract] [Full Text] [PDF]
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 Y. Wang, J. Mitchell, K. Moriyama, K.-j. Kim, M. Sharma, G.-x. Xie, and P. P. Palmer Age-Dependent Morphine Tolerance Development in the Rat Anesth. Analg., June 1, 2005; 100(6): 1733 - 1739. [Abstract] [Full Text] [PDF]
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