The effects of long-term opioid treatment on the immune system in chronic non-cancer pain patients: A systematic review.

BACKGROUND AND OBJECTIVE: Opioids have been increasingly prescribed for chronic non-cancer pain (CNCP). An association between long-term opioid treatment (L-TOT) of CNCP patients and suppression of both the innate and the adaptive immune system has been proposed. This systematic review aims at investigating the effects of L-TOT on the immune system in CNCP patients. DATABASES AND DATA TREATMENT: A systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and the CINAHL for relevant articles was performed. Studies examining measures of both the innate and the adaptive immune system in adult CNCP patients in L-TOT (≥4 weeks of intake) were included. Outcomes and the level of evidence were analysed. RESULTS: A total of 382 studies were identified; however, 376 were excluded (352 inappropriate methodology, 21 duplicates, three full-text could not be obtained) and one randomized controlled trial (RCT) and five cross-sectional studies were included and analysed. L-TOT compared with no treatment was associated with a lower percentage of natural killer (NK) cells, a lower absolute number of CD56bright NK cells, a higher absolute number of IL-2-activated NK cells and a higher concentration of IL-1ß as a response to toll-like receptor (TLR) agonists stimulation (Pam3CSK4, LPS, Imiquimod). No other significant differences were reported. Generalizability of the results was limited due to inconsistency of outcomes and an overall low quality of the studies. CONCLUSIONS: L-TOT may alter the immune system in CNCP patients, but the level of evidence is still weak. More studies are needed to clarify the impact of L-TOT on immune system function. SIGNIFICANCE: This systematic review found indication that long-term opioid treatment alters the immune system in chronic non-cancer pain patients. These alterations involved the NK cells and IL-1ß production. However, the level of evidence is weak.

Patient reported outcomes and neuropsychological testing in patients with chronic non-cancer pain in long-term opioid therapy: a pilot study.

Background and aims Opioid consumption has increased dramatically in patients with chronic non-cancer pain (CNCP), but long-term consequences are still unclear. The aim of this study is to investigate the effects of long-term opioid treatment on pain, cognition, mood, sleep and quality of life in CNCP patients. Methods In this cross-sectional pilot study, two groups of patients with CNCP treated in a multidisciplinary pain center were selected: (1) opioid group: ≥30 mg morphine equivalent/day for >4 weeks, and (2) control group: no opioid consumption for >4 weeks. Socio-demographic data, alcohol consumption, smoking habits and body mass index (BMI) were registered and pain (brief pain inventory), mood (Hospital Anxiety and Depression Scale), sleep (Pittsburgh Sleep Quality Index) and quality of life (RAND 36-Item Health Survey) were assessed. Continuous Reaction Time and the Digit Span Test were used to evaluate cognitive function. Data was analyzed with a Fisher's exact test and Wilcoxon two-sample test. Results Forty-two patients with CNCP were included (21 in each group). No differences regarding socio-demographics, smoking/alcohol habits and duration, type, or intensity of pain were found. More patients in the opioid group had significantly higher BMI (62% above BMI 25 vs. 33.3%, p = 0.042). Consequently, the subsequent data analyses were controlled for BMI. The two groups did not differ in pain, cognition, anxiety, depression, sleep or quality of life but both showed lower values than the normal standards. Further, the opioid group presented a tendency to lower ratings regarding pain and social function and performed below the normal cut off in the continuous reaction time. Conclusions No significant differences between the two groups were found regarding any of the above-mentioned variables. Interestingly, the patients assessed, regardless of taking opioids or not, could be classified with moderate pain intensity, anxiety and low quality of sleep and life compared to norm standards. Implications The findings of this pilot study suggested that long-term opioid treatment may influence pain and quality of life among CNCP patients. A larger cohort is needed to verify these findings.

Chronic Pain, Opioid Therapy, Sexual Desire, and Satisfaction in Sexual Life: A Population-Based Survey.

OBJECTIVES: Associations between chronic pain, opioid use, and sexual problems are acknowledged, but population-based investigations are sparse. Our study aimed at investigating the associations between chronic noncancer pain (CNCP), opioid use, lack of/low sexual desire, and dissatisfaction with sexual life. SUBJECTS: In 2013, 11,517 randomly selected individuals of the Danish population (18-74 years old without cancer) completed a self-administered questionnaire. METHODS: We classified CNCP: pain lasting six months or longer, short-term opioid use: one or more prescriptions the previous year, long-term opioid use: one or more prescriptions per month for six months the previous year. Sexual problems were assessed by four closed-ended questions. Data on dispensed opioids were retrieved from the Danish National Prescription Registry. Multiple logistic regression analysis was used to examine associations between CNCP, opioid use, and lack of/low sexual desire, and dissatisfaction in sexual life, presented as odds ratios (95% confidence intervals [CIs]). RESULTS: Compared with individuals without CNCP, individuals with CNCP in the long-term and short-term opioid use group and in the nonopioid use group were more likely to report a lack of/low sexual desire (OR = 2.64, 95% CI = 1.80-3.88; OR = 1.82, 95% CI = 1.39-2.38; OR = 1.46, 95% CI = 1.28-1.67, respectively) and dissatisfaction with sex life (OR = 1.69, 95% CI = 1.07-2.67; OR = 1.35, 95% CI = 1.00-1.82; OR = 1.38, 95% CI = 1.22-1.58, respectively). Compared with CNCP patients not using opioids, long-term opioid users with CNCP had statistically significant higher odds of reporting a lack of/low sexual desire (OR = 1.81, 95% CI = 1.23-2.68). CONCLUSIONS: Long-term opioid therapy for CNCP requires special attention due to its potential in suppressing sexual desire.

[Cannabinoids for neuropathic pain management].

Pharmacological treatment of neuropathic pain is associated with side effects and limited efficacy. Recently, the interest in cannabis-based medicine has led to legalisation of medical cannabis in some countries. The aim of this review is to evaluate the evidence of cannabinoids in neuropathic pain. Seventeen trials were identified; eight reported an analgesic efficacy of cannabis-based medicine, and the remaining trials showed no analgesic efficacy. Conclusions were limited by design of studies and short duration of treatment. Overall, the reduction in pain was minimal.

Assessment of cognitive function in patients with metastatic cancer: Are we using the right tools?

OBJECTIVE: This study aimed at analyzing the validity and reliability of the continuous reaction time (CRT) test, the finger-tapping test (FTT), the Digit Span Test (DST), the Trail Making Test - part B (TMTB), and the Mini-Mental State Examination (MMSE) in patients with metastatic cancer. METHOD: Eighty adult patients and 81 healthy controls were assessed between July of 2010 and November of 2015. The neuropsychological tests were analyzed regarding construct/discriminant/criterion validity and reliability. RESULTS: In terms of construct validity, it was not possible to estimate a model for the MMSE because of a skewed response distribution. For discriminant validity, patients were slower on two measures of the CRT (p = 0.00483, p = 0.00030) and FTT dominant hand (p = 0.00306). Regarding sensitivity and specificity, only the DST and TMTB seemed to predict cognitive deficit; however, the ROC curve areas were ≤ 0.73. In terms of criterion validity, there were few significant correlations between the tests and the sociodemographic and clinical variables, and for the most part were very weak. Reliability was deemed to be adequate for the TMTB, DST, and FTT. SIGNIFICANCE OF RESULTS: The findings of the full validation analyses were not clear-cut. However, CRT test, DST, FTT, and TMTB demonstrated partial positive results, indicating that these tests have good potential for use in clinical settings and require further study.

Healthcare professionals' agreement on clinical relevance of drug-related problems among elderly patients.

Background Disagreement among healthcare professionals on the clinical relevance of drug-related problems can lead to suboptimal treatment and increased healthcare costs. Elderly patients with chronic non-cancer pain and comorbidity are at increased risk of drug related problems compared to other patient groups due to complex medication regimes and transition of care. Objective To investigate the agreement among healthcare professionals on their classification of clinical relevance of drug-related problems in elderly patients with chronic non-cancer pain and comorbidity. Setting Multidisciplinary Pain Centre, Rigshospitalet, Copenhagen, Denmark. Method A pharmacist performed medication review on elderly patients with chronic non-cancer pain and comorbidity, identified their drug-related problems and classified these problems in accordance with an existing categorization system. A five-member clinical panel rated the drug-related problems' clinical relevance in accordance with a five-level rating scale, and their agreement was compared using Fleiss' κ. Main outcome measure Healthcare professionals' agreement on clinical relevance of drug related problems, using Fleiss' κ. Results Thirty patients were included in the study. A total of 162 drug related problems were identified, out of which 54% were of lower clinical relevance (level 0-2) and 46% of higher clinical relevance (level 3-4). Only slight agreement (κ = 0.12) was found between the panellists' classifications of clinical relevance using a five-level rating scale. Conclusion The clinical pharmacist identified drug related problems of lower and higher clinical relevance. Poor overall agreement on the severity of the drug related problems was found among the panelists.

[Strategies to avoid the risk of addiction when treating patients with chronic pains].

Addiction is a feared complication of long-term opioid treatment in patients with chronic pains. Strategies to decrease the risk of addiction include estimating of risk factors, establishing treatment goals realistic for pain and function, considering how to discontinue therapy if treatment goals are not achieved, avoiding administration forms with rapid absorption, using validated screening instruments and avoiding high opioid doses. If signs of addiction do occur, precautions to hinder overuse of opioid should be taken.

[Treatment of acute pain in opioid addicts].

The challenge of managing acute pain in opioid-addicted patients is a question of fully understanding the pharmacological effects of the illegal drugs and to prevent overdosing or withdrawal symptoms. It requires a thorough knowledge of the patient's daily consumption of legal and illegal drugs and an understanding obtained through an accepting and empathetic communication with the patient. Substitution management aims to prevent opioid withdrawal symptoms and is not a means of managing pain. When planning the pain management the patient must receive at least 25% of the daily methadone dose, recalculated into equipotent substitute morphine.

Does mutual compensation of the cognitive effects induced by pain and opioids exist? An experimental study.

RATIONALE: Studies have demonstrated that both pain and opioids have actions on the central nervous system that may interfere with cognitive function, but their effects have mainly been analysed separately and not as an integrated process. OBJECTIVE: The objective of this study is to test two hypotheses: (1) the analgesic effect of opioids improves cognitive function by decreasing pain, and (2) pain antagonizes cognitive effects of opioids. METHODS: Randomized, placebo-controlled, crossover study. Three experiments were conducted with 22 healthy males. Sustained attention, memory and motor function/attention/mental flexibility were evaluated by continuous reaction time (CRT), verbal fluency test (VFT) and trail making test-B (TMT-B), respectively. In the 1st experiment, the cognitive effects of experimental tonic pain of mild and moderate intensities produced by a computer-controlled pneumatic tourniquet cuff were assessed; in the 2nd, the effects of saline solution and remifentanil were assessed in the absence of pain; and in the 3rd experiment, the cognitive effects of moderate pain intensity relieved by remifentanil infusion were assessed followed by increasing pain to moderate intensity during a constant remifentanil infusion. RESULTS: The first two experiments demonstrated that pain and remifentanil impaired CRT. In the 3rd experiment, remifentanil infusion relieving pain significantly impaired CRT and further deterioration was noted following increasing pain intensity. CONCLUSION: Pain and remifentanil seemed to have additive deleterious cognitive effects. This study represents an initial step to enhance our basic understanding of some of the cognitive effects following a painful stimulus and an opioid infusion separately and combined in a sequence comparable to clinical settings.

Outcomes of follow-up visits to chronic nonmalignant pain patients.

Follow-up visits by clinical nurse specialists are beneficial for patients with various chronic conditions. It is unknown whether patients with chronic nonmalignant pain can achieve similar benefit. The aim of this study was to assess outcomes of follow-up visits by clinical nurse specialists to chronic nonmalignant pain patients regarding health-related quality of life (HRQoL), pain, opioid treatment, quality of sleep, and depression. A total of 102 patients were enrolled in a prospective randomized controlled trial during a 2-year period after discharge from multidisciplinary pain treatment and randomized to intervention or control group. Intervention group patients (n = 52) received home visits every fourth month for 2 years. The findings showed that HRQoL improved generally more in the intervention group. Statistically significant improvements were observed for physical function and bodily pain. Whereas the intervention group maintained the pain level on a visual analog scale, the control group reported more pain. During the observation period, the control group increased dosage of opioids whereas the intervention group maintained stable dosage. No significant effect on quality of life was found. Nurses identified signs of depression in 80% of their patients scoring depression on the simultaneous depression questionnaire, and thereby could refer patients to early treatment. Follow-up visits by clinical nurse specialists appeared to offer positive benefits to patients with chronic nonmalignant pain after discharge from multidisciplinary pain treatment. The intervention improved physical functioning, reduced bodily pain and pain intensity and prevented opioid dosage increase. Most episodes of depression were identified and referred to relevant treatment.

The burden of chronic pain: a cross-sectional survey focussing on diseases, immigration, and opioid use.

Chronic pain is currently considered a public health problem with high costs to the individual and society. To improve prevention and treatment of chronic pain, epidemiologic studies are mandatory for assessing chronic pain. The aims of this study were to estimate the prevalence of chronic pain in the adult Danish population and to analyze associated factors such as diseases, immigration, and opioid use. This cross-sectional survey combines individual-based information from the Danish Health Survey (2010) and official Danish health and socioeconomic, individual-based registers. The simple random sample consisted of 25,000 individuals (≥16 years old) living in Denmark. In all, 60.7% completed a mailed or online questionnaire. Associations were examined with multiple logistic regression analysis. The study population consisted of 14,925 individuals in whom a high prevalence of chronic pain (26.8%, 95% confidence interval: 26.1 to 27.5) and a high prevalence of opioid consumption (4.5%) were observed. Other aspects of particular note: (1) a higher prevalence of chronic pain occurred among individuals with cardiovascular and chronic pulmonary diseases than among individuals with cancer; and (2) individuals with a non-Western background reported a higher pain prevalence, higher pain intensities, and more widespread pain than individuals with Danish background; however, opioids were more frequently used by native Danes. The prevalence of chronic pain as well as opioid use in Denmark are alarmingly high, and the relevance of opioid consumption is unknown.

Non-analgesic effects of opioids: the cognitive effects of opioids in chronic pain of malignant and non-malignant origin. An update.

Opioids constitute the basis for pharmacological treatment of moderate to severe pain in cancer pain and non-cancer pain patients. Their action is mediated by the activation of opioid receptors, which integrates the pain modulation system with other effects in the central nervous system including cognition resulting in complex interactions between pain, opioids and cognition. The literature on this complexity is sparse and information regarding the cognitive effects of opioids in chronic pain patients is substantially lacking. Two previous systematic reviews on cancer pain and non-cancer pain patients only using controlled studies were updated. Fourteen controlled studies on the cognitive effects of opioids in chronic non-cancer pain patients and eleven controlled studies in cancer pain patients were included and analyzed. Opioid treatment involved slightly opposite outcomes in the two patient groups: no effects or worsening of cognitive function in cancer pain patients and no effect or improvements in the chronic non-cancer pain patients, however, due to methodological limitations and a huge variety of designs definite conclusions are difficult to draw from the studies. In studies of higher quality of evidence opioid induced deficits in cognitive functioning were associated with dose increase and the use of supplemental doses of opioids in cancer patients. Future perspectives should comprise the conduction of high quality randomized controlled trials (RCTs) involving relevant control groups and validated neuropsychological assessments tools before and after opioid treatment in order to further explore the complex interaction between pain, opioids and cognition.

Classification and identification of opioid addiction in chronic pain patients.

Addiction is a feared consequence of long-term opioid treatment of chronic pain patients. The ICD-10 and DSM-IV diagnostic addiction criteria may not be appropriate in these patients. Therefore Portenoy's criteria (PC) were launched. The aim was to estimate the prevalence of addiction, to investigate whether PC were applicable and to compare these criteria with the ICD-10 criteria. The study was cross-sectional and included 253 patients with chronic pain at a tertiary pain centre. Patients were screened for addiction by a physician and a nurse. The addiction prevalence was 14.4% according to ICD-10 and 19.3% according to PC. A significant difference between the prevalence of addiction according to ICD-10 and to PC was found. The inter-rater reliability was 0.95 for ICD-10 and 0.93 for PC. The sensitivity of PC was 0.85 and the specificity was 0.96. According to PC patients classified as addicted were treated with significantly higher opioid doses, drank more alcohol, smoked more tobacco, used benzodiazepines and had higher levels of depression. According to ICD-10 patients classified as addicted used higher doses of opioids, drank more alcohol and had higher scores of anxiety and depression. High opioid doses, concomitant use of alcohol and younger age were risk factors. The risk profile for PC was different to ICD-10 by adding risk factors as concomitant use of benzodiazepines, having depression and low educational level. PC seems to be appropriate for diagnosing addiction in opioid treated pain patients and seems to be more sensitive and specific than ICD-10 criteria.

An update on the role of opioids in the management of chronic pain of nonmalignant origin.

PURPOSE OF REVIEW: To summarize and reflect over primarily recent epidemiological and randomized controlled trials in opioid-treated chronic nonmalignant pain patients, focusing on effects, side effects, risks and long-term consequences of the treatment. RECENT FINDINGS: In the western world opioids are increasingly being used for long-term treatment of chronic nonmalignant pain. While the long-term benefits of opioids regarding pain relief, functional capacity and health-related quality of life still remain to be proven, studies are emerging that describe serious long-term consequences such as addiction, opioid-induced hyperalgesia, cognitive disorders, and suppression of the immune and reproductive systems. SUMMARY: Much more research is needed concerning long-time effects and consequences of opioid therapy in chronic nonmalignant pain patients; however, some clear warning signals have been sent out within recent years.

[Differences in the prescription of analgesics in the treatment of cancer pain in six Danish pain treatment units]. / Forskelle på ordinationsmønstret af analgetika ved behandling af cancersmerter på seks danske smertebehandlingsenheder.

30-40% of cancer patients suffer from pain at diagnosis while 70-80% of patients at progressed stages of the disease suffer from pain. Background pain is treated with long-acting opioids. Breakthrough pain can be treated with shorter acting non-opioid analgesics or opioids. The aim of this study was to describe the medical treatment of pain in cancer patients in connection with six Danish hospital units with special expertise in pain treatment. Differences in the prescription of analgesics were studied. The study was performed as a cross section study of prescribed analgesics. Data was collected by reviewing medical records. The study included 347 patients. A total of 278 patients out of 347 were treated with opioids for background pains. A significant difference was found (P < 0.001) in the frequency of prescribing morphine, oxycodone and fentanyl. For the treatment of background pain secondary analgesics were prescribed for 40% of the patients while 50% of the patients were treated with paracetamol and/or NSAID. According to the medical records 79% of the patients were prescribed analgesics for breakthrough pain. 73% of the 347 patients had strong opioids prescribed for breakthrough pain. For the treatment of background pain opioids were prescribed for the majority of the cancer patients. Morphine and oxycodone were prescribed most frequently. Secondary analgesics and paracetamol and/or NSAID were also prescribed for background pain. The strong opioids were prescribed for the treatment of breakthrough pain. Differences in the prescription of analgesics between the six hospital units were observed in this study.

Addiction to opioids in chronic pain patients: a literature review.

Opioids have proven very useful for treatment of acute pain and cancer pain, and in the developed countries opioids are increasingly used for treatment of chronic non-malignant pain patients as well. This literature review aims at giving an overview of definitions, mechanisms, diagnostic criteria, incidence and prevalence of addiction in opioid treated pain patients, screening tools for assessing opioid addiction in chronic pain patients and recommendations regarding addiction problems in national and international guidelines for opioid treatment in cancer patients and chronic non-malignant pain patients. The review indicates that the prevalence of addiction varied from 0% up to 50% in chronic non-malignant pain patients, and from 0% to 7.7% in cancer patients depending of the subpopulation studied and the criteria used. The risk of addiction has to be considered when initiating long-term opioid treatment as addiction may result in poor pain control. Several screening tools were identified, but only a few were thoroughly validated with respect to validity and reliability. Most of the identified guidelines mention addiction as a potential problem. The guidelines in cancer pain management are concerned with the fact that pain may be under treated because of fear of addiction, and the guidelines in management of non-malignant pain patients include warnings of addiction. According to the literature, it seems appropriate and necessary to be aware of the problems associated with addiction during long-term opioid treatment, and specialised treatment facilities for pain management or addiction medicine should be consulted in these cases.

10-year follow-up of chronic non-malignant pain patients: opioid use, health related quality of life and health care utilization.

BACKGROUND: In Denmark, opioids have been used liberally for many years in the treatment of non-malignant pain, but long-term consequences as tolerance and influence on health related quality of life remain unknown. AIM: Adherence to medical treatment, opioid dose escalation, health related quality of life, anxiety, depression, coping strategies and health care utilization were evaluated in chronic pain patients 10 years after treatment in a multidisciplinary pain centre. METHODS: Information was gathered from medical records, postal questionnaires and a central hospital register. RESULTS: Opioid dose escalation occurred in only a few patients. Increase and decrease in opioid dose were almost equally frequent. Sixty percent of those discharged on long acting opioids were still on that treatment at follow-up. Twenty-eight percent of the patients initiated opioid treatment after discharge from the pain centre. Occupational status was identified as a determining factor for future opioid use. Opioid users had a lower health related quality of life, higher occurrence of depression and more frequent use of coping strategies like 'Catastrophizing' and 'Hoping and Praying'. Adjuvant analgesics were highly discontinued. Multidisciplinary pain treatment reduced the number of hospital admissions and in-hospital days. CONCLUSION: We recommend that future research on opioid treatment does not only focus on biological issues. The effect of opioids needs to be viewed in a much more complex context where consequences like health related quality of life, depression and the role of various coping strategies are included.

Neuropsychological assessment of chronic non-malignant pain patients treated in a multidisciplinary pain centre.

The aim of the study was to investigate the influence of pain, sedation, pain medications and socio-demographics on cognitive functioning in chronic non-malignant pain patients. Chronic non-malignant pain patients (N=91) treated in a multidisciplinary pain centre were compared with age and sex matched healthy volunteers (N=64). Furthermore four subgroups of patients were examined: Group 1 (N=21) received no pain medications, group 2 (N=19) were in long-term oral opioid treatment, group 3 (N=18) were treated with antidepressants and/or anticonvulsants and group 4 (N=33) were treated with a combination of long-term oral opioids and antidepressants and/or anticonvulsants. Assessments comprised pain (PVAS) and sedation (SVAS), Continuous Reaction Time (CRT) testing for sustained attention, Finger Tapping Test (FTT) testing for psychomotor speed, Paced Auditory Serial Addition Task (PASAT) testing for information processing and working memory and Mini Mental State Examination (MMSE). CRT and FTT were impaired in the total patient sample. Treatment with opioids was associated with poorer performance of PASAT. High scores of PVAS and SVAS were associated with poor performance of PASAT and CRT, respectively. MMSE seems to be too insensitive for detecting the milder forms of cognitive impairment found in chronic non-malignant patients.