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Persistent pain and cognitive impairment are common in older adults. Memory and mental flexibility are cognitive domains which may be vulnerable in the aging brain. We were interested in examining the effects of persistent pain and opioid use on cognition in community dwelling, non-demented older adults.
Older Adult Pain Management Program.
57 new patients (mean age 76.1) were recruited to describe 1) rates of persistent pain conditions and pain intensity, 2) cognition (memory and mental flexibility), 3) rates and severity of depression, and 4) sleep quality. All patients had non-malignant pain for at least 3 months. Pain intensity was measured with the McGill Pain Questionnaire. Diagnosis of depression was via the Patient Health Questionnaire and depression severity assessed with the Hamilton Rating Scale for Depression. Cognition was assessed with: 1) Mini Mental State Examination, 2) number-letter-switching and motor speed trail-making subtests, 3) Digit Symbol Subtest of the WAIS-R, and 4) free and paired recall of the WAIS-R. To determine which variables predicted poorer outcomes on mental flexibility tests, these variables were entered into a multiple regression.
Pain severity was associated with impaired number-letter switching (r = −0.42, p = 0.002). Multiple regression showed pain severity was associated with impaired mental flexibility (parameter estimate = −0.29 (t = −2.00), p = 0.05). Patients taking opioids had worse memory (t = 2.17, df = 39, p = 0.04).
In community-dwelling older adults, pain severity is associated with impaired mental flexibility. In addition, opioids may increase memory problems.
Older adults currently constitute more than 12% of the United States' population. Within the next 30 years, the number of older adults is expected to double, creating a potential crisis situation regarding provision of healthcare services (1). In community-dwelling older adults, the prevalence of pain experienced every day for at least three to six months has been estimated to occur at rates of up to 31% (2). Other studies have estimated that up to 70–85% of people aged 65 and older experience a significant health problem that predisposes them to persistent pain (3, 4).
Persistent pain in older adults is related to sleep difficulties, increased medication usage, depression, decreased mobility, and lower self-perceived quality of health (5). Thus, persistent pain in older adults may add to an already burdened public health system (6). In addition, pain, and medications such as opioids used in its treatment, have been reported to have adverse effects on cognition (7–11) in mixed age groups. Declines across the adult life span have been universally observed in both cross-sectional and longitudinal studies of cognitive aging on the performance of tasks that require different perceptual or cognitive processes (12). Older adults may be at greater risk of cognitive impairment from pain and opioids, which may further degrade cognitive abilities that are already stressed by age-related cognitive decline, pre-clinical dementia, and polypharmacy (e.g., anticholinergic burden).
Cognition is comprised of numerous domains. Several studies (13–16) suggest that normal aging is associated with mild decline in executive function (defined as a cluster of high-order capacities, which include selective attention, the ability to shift between unique sets of objects or concepts, behavioral planning and response inhibition, and the manipulation of information in problem-solving tasks). Moreover, memory disturbance (17) and executive dysfunction (18) are domains associated with the later development of dementia (19); indeed, memory problems are required for the diagnosis of dementia (20). Deficits in these areas may be present years before functional impairment is present (19). The burden of persistent pain and/or opioid analgesics in this population may lead to further dysfunction in these vulnerable areas.
We hypothesized that in a sample of non-demented community dwelling older adults who had recently begun treatment at a pain clinic, severity of pain would be positively correlated with impaired memory. We also hypothesized that pain severity would be positively correlated with deficits in mental flexibility (i.e., suggesting an association with executive dysfunction). In addition, we hypothesized that patients treated with opioids would have more memory impairment and difficulty with mental flexibility than patients not treated with these agents.
Subjects were recruited from the Older Adult Pain Management Program (OAPMP) of the Pain Evaluation and Treatment Institute (PETI), a component of the University of Pittsburgh Medical Center. The OAPMP is a university-based multidisciplinary pain clinic for older adults. All fifty-seven of the subjects were referred from primary care physicians in the community.
To encourage recruitment, flyers describing the study were posted in the consulting rooms and brochures were placed in the patient waiting room. The senior author (DKW) is medical director of the OAPMP. Up to the first three new patients seen at the clinic each week who met entry inclusion and exclusion criteria were asked if they would be interested in participating in a study “to better understand older adults who live with pain, so that we can ultimately develop new treatments.” If the patient agreed to participate, he or she either contacted the investigators directly, or consented to have the research team contact them to set up an evaluation. Potential subjects were informed that benefits were mental health referrals if indicated, and reimbursement of $30 for their time.
Inclusion criteria for recruited subjects included persistent pain of any non-malignant etiology for at least three months duration. All subjects were 60 or older, willing and able to provide informed consent, and English-speaking. In addition, all had corrected visual ability that enabled reading of newspaper headlines and hearing capacity that was adequate to respond to a raised conversational voice. All fifty-seven subjects were new patients at PETI. Research assessments were scheduled within two weeks to reduce the effect of newly prescribed treatments on the neuropsychological and other assessments. Patients were excluded if they had ever been diagnosed with dementia. All subjects were required to have a Mini Mental State Exam score of ≥ 24 to participate.
All subjects underwent an assessment of their pain chief complaint, including severity of pain, depression, medical comorbidity, sleep quality, and neuropsychological functioning. The study was approved by the University of Pittsburgh Institutional Review Board. Written informed consent was obtained from all patients.
Quality and intensity of pain were measured with the McGill Pain Questionnaire Short Form (MPQ-SF). The MPQ-SF has been validated in community dwelling older adults (21, 22). The MPQ-SF has a Visual Analog Scale (VAS) component which assesses current severity of pain. The Cronbach coefficient alpha for the MPQ-SF total score was 0.81.
The Patient Health Questionnaire (PHQ) (23) was administered to identify subjects with DSM-IV-defined major depression. The PHQ has been reported to have an overall accuracy rate of 85%, 75% sensitivity, and 90% specificity (23). The Hamilton Rating Scale for Depression (17-item) (24) assessed severity of depression.
Medical Comorbidity was measured with the Cumulative Illness Rating Scale adapted for use with geriatrics (CIRS-G) (25, 26). The CIRS-G can be successfully applied in both medically and psychiatrically impaired older adult subjects, with good interrater reliability and face validity (25).
The Pittsburgh Sleep Quality Index (PSQI)(27) was used to assess sleep quality and disturbances over the past four weeks. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. A global PSQI score > 5 has been shown to distinguish good and poor sleepers. The Cronbach alpha for the PSQI using all seven subscales was 0.72.
Mini-Mental Status Exam (MMSE) (28). The MMSE is a well-known and widely used brief mental status test of cognitive impairment in older adults.
Mental flexibility was assessed with the Trail Making Test of the Delis-Kaplan Executive Function System (D-KEFS) (29). This test is similar to the traditional Trail Making Test, but is comprised of five subtests that may be used to correct for processes other than mental flexibility that may be contributing to a slow response time or to set-shifting errors. These tests are also age-adjusted. The D-KEFS Trail Making subtests administered to patients include the number-letter switching condition (similar to the traditional Trails B) that is a measure of mental flexibility. The other is a test of motor speed (similar to the traditional Trails A).
Digit Symbol Subtest (DSST) (WAIS-R): The DSST of the Wechsler Adult Intelligence Scales – Revised (30) is highly sensitive to neuropsychological dysfunction (31) and is another probe of mental flexibility. This visuoperceptual decoding task requires the subject to associate single-digit numbers with unfamiliar symbols. A stimulus set of nine printed digit-symbol pairs is presented above rows of numbers without the appropriate symbols. The subject is instructed to draw the correct symbol below each of the numbers using the digit-symbol code presented above. The score is based on the number of substitutions completed within 90-seconds.
Memory was assessed with the incidental learning tests administered immediately following the DSST. Paired-recall involves completing a number of Digit Symbol items without access to the code key; free recall, simply reproducing the symbols from memory. These tests of memory were only administered if patients completed four rows of the DSST test within 120 seconds. The reason for this was to standardize the time each patient was exposed to the digit/symbol stimuli.
The mean, standard deviation, median, and range of values were calculated for the demographic, pain, and cognitive variables. Pearson correlation coefficients between the pain and cognitive variables were calculated. Multiple regression analyses were then performed to further examine the relationship between pain and cognition and to rule out the effect of potential clinical confounders. In the forced multiple regression models, dependent variables were mental flexibility and psychomotor speed. Independent variables were depression severity, pain severity, opioid use, sleep quality, medical burden, and education.
Pain severity, rates of depression diagnosis and severity and cognition as a function of opioid use was tested with chi-square tests for categorical variables and t-tests for continuous variables.
The clinical and demographic characteristics of the sample are listed in Table 1. Pain diagnoses are also listed in Table 1 in descending order of prevalence. Eighty-eight percent of patients (n=50) received more than one pain diagnosis at initial evaluation. The mean (total) score for the MPQ-SF was 17.3 (SD ± 9.0, range 2–39). The mean score for the VAS was 57.7 (SD ± 25.7, range 2–100).
Table 2 lists the descriptive data for each of the cognitive measures. We observed an association between the MPQ-SF and the D-KEFS Trails number-letter-switching test (r = −0.42, n = 52 p = 0.002). More severe pain was associated with increased impairment on number-letter switching. A positive correlation between pain severity (MPQ-SF) and memory (paired recall test) was not statistically significant. We also found no association between either the total score of the MPQ-SF and the MMSE (r = −0.06, n = 54, p = 0.65) or the free recall test (r = −0.01, n = 41, p = 0.93). We failed to detect an association between pain severity and either the DSST (r = −0.12, n = 51, p = 0.40) or the D-KEFS Trails test of motor speed (r = −0.12, n = 52, p = 0.39).
Three forced multiple regression models which included pain severity, depression severity, opioid use, sleep impairment, medical comorbidity, and education level as independent variables and mental flexibility (digit symbol or number letter switching) and psychomotor speed as dependent variables also found pain to be the only variable associated with mental flexibility (p = 0.05) (Model F = 2.69, df = 6,45, p = 0.03, R2 = 0.26) (Table 3). Using this model, pain severity was not significantly correlated with psychomotor speed. Memory was not included in the multiple regression model because no univariate correlation between pain severity and memory was found.
Thirty (52.6%) patients were taking opioid analgesics at the time of the neuropsychological assessment. Before comparing opioid versus non-opioid treated patients on measures of cognition, a t-test was performed to determine whether the two groups had different pain severity at the time of testing. Patients prescribed opioids had a mean MPQ-SF score of 18.9 (SD ± 8.3) and patients who were not prescribed opioids had a mean MPQ-SF of 15.4 (SD ± 9.6) (t = −1.44, df = 55, p = 0.15). In addition, we did not detect a difference in either the rate of respondents who screened positive for major depression (chi-square=3.05, df=1, p=0.08) or any depression diagnosis ([major or minor], chi-square = 1.27, d f= 1, p = 0.26) between the two treatment groups. However, the patients taking opioids on average had higher HRSD scores (mean = 10.8, SD ± 5.9) than patients not taking opioids (mean = 6.9 ± 5.8) (t = −2.49, d f= 54, p = 0.02).
Subjects taking opioid analgesics had more difficulty with unprompted memory than those who did not, as assessed with the free recall test (Table 4). No other differences in cognition were found between the two groups.
The results suggest that in non-demented community dwelling older adults receiving treatment at a specialty pain clinic, pain severity was associated with impaired cognition. In particular, pain severity was negatively associated with mental flexibility, which suggests impaired executive functioning. Using multiple regression to control for possible clinical confounders (e.g., depressive symptoms, opioid use, medical comorbidity, education level), a significant association (p = 0.05) was found, supporting the association between pain severity and executive impairment.
When studying cognition, restricting the age range may increase the clinical utility of the findings because of the known differences between young and old patients (32, 33). In our sample of older adults, it appears that mental flexibility (i.e., a test of executive function) becomes more impaired as pain severity increases. A possible reason for this could be that as pain becomes more severe, some older adults may not be able to “shut down” nociceptive interference with higher cognitive functions, resulting in executive impairment. Because of both the limited sample size and the lack of a correlation between pain severity and psychomotor slowing, in the analysis we did not adjust for the possible contribution of psychomotor slowing.
After controlling for both those patients who screened positive for depression at baseline and for degree of pain severity, we found that patients receiving opioids scored worse on the test of free recall. Other studies have shown opioids to be associated with impaired performance on neuropsychological testing. For instance, opioids have been shown to be associated with poor performance on a test of both working memory and information processing (34). In that double blind, placebo controlled study of the cognitive effects of immediate-release morphine on chronic pain (cancer and non-cancer), patients who were already receiving sustained-release opioids experienced a negative effect on both anterograde and retrograde memory when immediate-release morphine was added to their treatment. In addition, immediate-release morphine reduced performance on the number-letter switching task (i.e., mental flexibility) (35). A limitation to our study is that we did not quantify whether patients were prescribed immediate release or sustained release opioids, and if they were taking a combination of formulations. Nevertheless, in our survey, it appears that opioids negatively affects the memory of older adults with persistent pain.
We note that a recent comprehensive review on the potential association between opioids and cognition among patients with chronic cancer or non-cancer pain (36) reported relatively few differences in cognitive performance on opioids when compared with baseline performance or with the performance of a comparable pain population not on opioids; however, the studies reviewed were of mixed age groups. The aging brain is uniquely vulnerable to both polypharmacy (e.g., antidepressants and benzodiazepines have been found to synergistically worsen cognition in older adults (37)), and to the anticholinergic burden of many medications (38).
These findings have implications for the treatment of older adults with persistent pain at both multidisciplinary chronic pain programs as well as in primary care, where most older patients receive care for painful conditions (39). A useful strategy of chronic pain treatment programs may combine elements of cognitive-behavioral therapy (CBT), physical and occupational therapies, and medical management. How chronic pain is perceived and handled influences psychological and physical adjustment (40). The severity and debilitating effects of chronic pain may be mitigated as patients come to view pain and discomfort less as an overwhelming catastrophe and more as a controllable and manageable condition (41). However, if older adults with more severe pain experience cognitive problems, in particular executive dysfunction and perhaps impaired memory, CBT may be ineffective, and new approaches to treatment are needed. For example, caregivers (e.g., spouses, adult children) may need to be invited to participate in care to assure treatment recommendations are understood and followed. Patients may also benefit from written treatment instructions to reduce their chance of making an error or forgetting specific instructions.
If a patient’s cognition limits his or her abilities to fully participate in and benefit from CBT, a more simplified psychosocial intervention may be indicated. One option would be Problem Solving Therapy (PST), which has been used in the treatment of both somatic conditions (42–46) and depression with executive dysfunction (47, 48), and has been shown to be a structured, collaborative treatment that identifies specific problems and helps the patient overcome them. PST consists of several stages which include: (1) identification and clarification of the problem; (2) setting clear goals; (3) forming alternative and selecting preferred solutions; (4) clarification of the necessary steps to implement the solution; and (5) evaluation of progress (49). PST is in many ways similar to CBT. However, the focus is more behavioral, which may work better in a population with varying degrees of cognitive dysfunction. PST has been effectively delivered in busy clinic settings, and one-on-one educational sessions that teaches problem-solving skills have benefited both family caregivers and patients with cancer (50). PST also has been modified specifically for cognitively impaired patients (44).
In summary, both pain intensity and opioid use in non-demented persistent pain patients are associated with negative effects on cognition. In particular, mental flexibility and memory are domains at particular risk of impairment, perhaps because these are already vulnerable areas of cognition in the aging brain. Clinicians need to be aware that both persistent pain, and opioids used to treat it, may cause or worsen subtle cognitive deficits in the aging brain, as these are both reversible causes of cognitive impairment.