After two decades of liberal prescribing of opioids, there has been an increasing recognition of problems connected to the prolonged use of opioids for chronic pain. The aim of my thesis was to explore some consequences of long-term opioid treatment for chronic pain such as problematic opioid use, endocrine disorders, tolerance and genetic variations in pain and opioid response. Sixty patients with severe pain and problematic opioid use were treated with a structured methadone programme. Risk factors were musculoskeletal pain, psychiatric co-morbidity and previous addiction. Treatment resulted in good pain relief and improved quality of life, but function was impaired by side effects indicating endocrine dysregulation. The possibility of opioid-induced endocrine dysfunction was explored in the second paper, where 40 pain patients treated with strong opioids and 20 pain patients without treatment of strong opioids were investigated. The opioid-treated patients had significantly higher incidence of endocrine disturbance affecting gonadal and adrenal function and prolactin levels. The functionality of the μ-receptor after long-term treatment with morphine, saline and naloxone was explored in a cell-line expressing the μ-receptor. After one and four weeks of treatment the binding was tested with morphine, methadone, fentanyl and DAMGO and function measured by GTP γ-assay. The binding of DAMGO was significantly diminished after 4 weeks in cells treated with morphine compared with saline and naloxone. Genetic variation in three genes with functional impact on opioid response and pain sensitivity was investigated in 80 patients with chronic low-back pain and differential opioid sensitivity and in 56 healthy controls. The results indicated a higher incidence of opioid-related side effects and gender differences in patients with the minor allele of the ABCB1 gene, a correlation between increased opioid sensitivity and the major CACNA2D2 allele and a possible relationship between intrinsic protection against chronic pain and the minor allele of OPRM1.

INTRODUCTION: Pain is common in cancer. Pain can present at the time of diagnosis or it can develop during treatment. Cancer-related chronic pain is often treated with long-term (3 or more consecutive refills) opioid prescriptions. Opioids are a controlled substance and are thus regulated at the federal, state, and local levels. OBJECTIVES: The first goal of this study is to examine Boston Children's Hospital's general compliance with federal, state, and local opioid prescribing policies. The second goal of this study is to distinguish cancer patients requiring long-term opioids from non-cancer patients requiring long-term opioids. METHODS: This study was a retrospective chart review using summative qualitative content analysis. This is the process where content is grouped into themes and then is further quantified within each theme. RESULTS: Documents required to ensure compliance with opioid prescribing regulations at the local level are not always well documented. These include the Long-Term Opioid Agreement and the risk evaluation of opioid misuse and abuse using one of several tools annually. At Boston Children's Hospital (BCH), the CRAFFT (car, relax, alone, forget, friends, trouble) questionnaires are used for this purpose. State policies require that, if a patient is not seen at least once every 6 months, physicians must document explicitly why a clinic visit was not possible. These reasons are never clearly listed within the medical record. Additionally, data shows that cancer patients using long-term opioids tend to be younger (mean age 14.4) than non-cancer patients (mean age 26.7). Cancer pain can present either at diagnosis, during treatment, or be present during both. Where n=16 cancer patients, 62.53% experienced pain both at diagnosis and during treatment, 25% experienced pain only during treatment, and 12.5% experience pain only at diagnosis. Finally, data also show that anxiety and comorbidity are common, 34.6% of n=29 patients in both cancer and non-cancer patients using long-term opioids. 34.6% of patients experienced comorbidities of either anxiety or depression. CONCLUSIONS: Despite these discrepancies with documentation, review of patients on long-term opioids revealed those with complex and painful medical conditions generally had valid reasons to require long-term opioids. Therefore, there is no evidence that BCH prescribers are involved in any sort of inappropriate opioid prescribing. Finally, no meaningful conclusions were drawn from data regarding pain score and weight because of inconsistencies in electronic medical record documentation in these areas.

Background: Opioids are often used in nursing homes to manage non-malignant pain, but little is known about their long-term use, initiation, and comparative safety. Methods: We used the Minimum Data Set 3.0 from 2011-2013 merged to Medicare and facility characteristics data to study opioid use and safety among older, long-stay residents. The specific aims were to examine the 1) prevalence of long-term opioid use; 2) geographic variation in the initiation of commonly used opioids (oxycodone, hydrocodone, tramadol); and 3) comparative safety of commonly used opioids and fracture hospitalizations. Results: One in seven long-stay residents were prescribed opioids long-term. There was extensive geographic variation in the initiation of commonly used opioids, with oxycodone (9.4%) initiated less frequently than hydrocodone (56.2%) or tramadol (34.5%) but varying most extensively across the United States, with the majority of variation in prescribing explained by state of residence. Compared to hydrocodone initiators (7.9 fracture hospitalizations per 100-person years), those initiating tramadol had lower rates of fracture hospitalizations (subdistribution hazard ratio [HRSD] = 0.67, 95% Confidence Interval [CI]: 0.56-0.80), whereas oxycodone initiators had similar rates of fracture hospitalizations (HRSD=1.08, 95% CI: 0.79-1.48). Conclusion: The prevalence of long-term opioid use was twice as common in nursing homes as community settings, with initiation patterns varying extensively by region and being strongly driven by state of residence. Although initiating tramadol was associated with lower rates of fractures than hydrocodone, questions on opioid risks and benefits remain and are especially pertinent given the high mortality rates in this population.

BACKGROUND: Chronic low back pain (CLBP) is the leading cause of disability in the United States. People suffering from CLBP often have multiple comorbidities including depression, anxiety, and substance use disorder (SUD). Although the opioid epidemic has intensified the search for new treatment options, both pharmacological and other, opioids still remain the most common treatment for chronic pain. Long-term opioid therapy (LTOT) has been shown to lead to opioid-induced hyperalgesia (OIH), an increased sensitivity to painful stimuli. It remains unclear, however, the extent to which reductions in opioid dose impact OIH. METHODS: This is a longitudinal cohort study whose primary aim is to determine how changes in opioid doses are associated with changes in psychosocial and quantitative sensory testing (QST) variables. Participants were 24 adults with CLBP being treated with LTOT and visits were conducted on a monthly basis for six months. All 24 participants were included in the analysis of demographic and psychosocial variables (disability, anxiety, depression, opioid misuse, pain severity, pain interference, and catastrophizing). A subset of 13 participants were included in the analysis of QST variables. RESULTS: We found that pressure pain thresholds at the thumb and the trapezius, and heat pain threshold significantly (p < 0.05) improved between visit 1 and visit 6. We also found that a decrease in morphine equivalent doses (MED) is correlated (coefficient > 0.2) with improvements in punctuate probe rating, pain pressure at the thumb, and maximum cold ratings. DISCUSSION: Our results show that reductions in opioid dose are associated with reduced pain sensitivity, even while the psychosocial variables studied (including subjective pain score, depression, and anxiety) remain stable.

<p>  </p> <p><strong>Background:</strong> Older adults have a higher prevalence of pain compared to other age groups and are more likely to become long-term opioid users. The clinical benefits of long-term opioid therapy (LTOT) are not clearly known, however, LTOT has been found to increase the risk of all-cause mortality, opioid overdose, constipation, fractures, and myocardial infarction. </p> <p><br></p> <p><strong>Objective: </strong>The study was conducted to estimate the incidence of LTOT and risk factors associated with LTOT in older adults aged 65 years and older.</p> <p><br></p> <p><strong>Methods:</strong> This was a retrospective cohort study based on Medicare claims data obtained from Research Data Assistance Center (ResDAC). Opioid naïve older adults filling an opioid prescription between 2014 and 2016 were included. The outcome was LTOT which was defined as an opioid use episode lasting longer than 90 days and having more than 60 cumulative days of supply. The independent variables (risk factors) were patient characteristics (demographics, comorbidities, substance use disorders), characteristics of initial/index opioid dispensed (opioid type, duration of action of opioid, opioid dose, number of days’ supply, concomitant medications), and pain conditions. Multivariable logistic regression was performed to assess the association between the risk factors and LTOT. To address statistical interactions among variables, secondary analyses were conducted after stratifying the dataset by pain conditions.</p> <p><br></p> <p><strong>Results:</strong> Among 162,287 opioid naive patients, 10,296 (6.3%) transitioned to LTOT. Demographic characteristics associated with LTOT were age greater than 85 years (adjusted odds ratios [AOR]: 1.1, 95% confidence interval [CI]:1.03-1.18) and being black (AOR: 1.11, 95% CI: 1.01-1.22). Risk factors related to substance use disorders included drug use disorder (AOR: 1.59, 95% CI: 1.30-1.95), alcohol use disorder (AOR: 1.26, 95% CI: 1.06-1.49), tobacco use disorder (AOR: 1.33, 95% CI: 1.21-1.45), and a history of opioid use disorder (OUD) (AOR: 1.63, 95% CI: 1.34-1.98). Patients with more than 5 comorbidities had 1.56 times higher odds (95% CI: 1.46-1.66) of LTOT compared to patients with 0-2 comorbidities. Characteristics of initial/index opioid associated with LTOT were dispensing long-acting opioids (AOR: 1.73, 95% CI: 1.22-2.46), concomitant use of benzodiazepines (AOR: 1.19, 95% CI: 1.11-1.28), gabapentinoids (AOR: 1.59, 95% CI: 1.49-1.69), and non-steroidal anti-inflammatory drugs (NSAIDs) (AOR: 1.23, 95% CI: 1.16-1.30). Starting therapy with tramadol increased the odds of LTOT compared to hydrocodone in patients with osteoarthritis and joint pain (AOR: 1.22, 95% CI: 1.06-1.41) as well as abdominal and bowel pain (AOR: 1.53, 95% CI: 1.05- 2.22). However, starting therapy with oxycodone decreased the odds of LTOT in patients with osteoarthritis and joint pain (AOR: 0.69, 95% CI: 0.53-0.90). For all pain conditions, initial opioid supply of ≥30 days led to 10-16 times higher odds of LTOT compared to days’ supply of 1-3 days.</p> <p><br></p> <p><strong>Conclusions:</strong> Higher age, black race, comorbidities, substance use disorders, and history of OUD are the patient-related risk factors of LTOT in older adults. Moreover, specific patterns of initial/index opioid prescription/dispensing such as greater number of days’ supply, dispensing long-acting opioids, and concomitant use of benzodiazepines, gabapentinoids, and NSAIDs increase the odds of LTOT. Prescribers should take these factors into consideration when prescribing opioids to older adults.</p>