Opioid tapering and mental health crisis in older adults.

BACKGROUND: Opioid tapering and discontinuation have increased in recent years with the implementation of national prescribing guidelines. This study aimed to examine the relationship between opioid tapering velocity and mental health crisis events in older Medicare beneficiaries. METHODS: A nested case-control study was conducted using the 2012-2018, 5% national Medicare claims data. Older adults with chronic non-cancer pain (CNCP) who were receiving long-term opioid therapy (LTOT) were included in the study. Cases were defined as individuals experiencing mental health crisis events; controls were identified using incidence density sampling. The opioid tapering velocity was measured in the 120-day hazard period that yielded a monthly percentage of dose change. Conditional logistic regression was used to assess the relationship of interest. RESULTS: A total of 42 091 older adults with CNCP were eligible for the study. Cases (n = 952) were matched with controls in a 1:2 ratio based on age (±1 year) and time of cohort entry (±30 days). A higher percentage of controls (67.65%) were on steady dose compared with cases (59.03%). In the adjusted model, tapering (aOR = 1.36; 95% CI: 1.02-1.83), rapid tapering (aOR = 1.45; 95% CI: 1.11-1.91), and dose escalation (aOR = 1.78; 95% CI: 1.32-2.39) were significantly associated with the mental health crisis, compared with steady dose. CONCLUSION: Both opioid tapering and dose escalation are associated with mental health crisis events. Patient-driven and gradual dose tapering, as recommended by prescribing guidelines, should be promoted to prevent mental health crisis events among older adults on LTOT.

Association Between Smoking Status and Opioid Dose in Prescriptions Written for Breast Cancer-related Pain.

BACKGROUND: Cancer-related pain has historically been undertreated. Prescription opioids have been shown to be an integral part of the treatment of cancer pain. Despite the significant amount of scientific evidence that smoking is associated with variation in pain expression and opioid misuse in both cancer and non-cancer populations, little is known about the association between smoking status and opioid utilization in cancer populations. OBJECTIVES: To assess the association between smoking status and high-risk opioid-prescribing behaviors of oncologists prescribing opioids in the outpatient setting to patients with breast cancer-related pain. STUDY DESIGN: A retrospective cross-sectional study of opioid prescriptions written by oncologists for breast cancer-related pain was conducted using the Patient Cohort Explorer (PCE) database at the University of Mississippi Medical Center (UMMC) from March 15, 2015 to March 15, 2017. SETTING: Tertiary academic medical center. METHODS: De-identified data from UMMC PCE were utilized for this study. Patient-level information, such as age, gender, race, insurance status, and smoking status, were also selected for each prescription. Prescription-level data, such as name of opioid, dose, frequency, route, and primary diagnosis, were also obtained. Prescriptions were included if they are written in the outpatient setting, for breast cancer-related pain, and for women 18 years or older. Prescriptions were excluded if they were written by a specialist other than a medical oncologist or if the information necessary to calculate morphine milligram equivalence (MME) was missing. RESULTS: The sample consisted of 577 opioid prescriptions that were written in the outpatient setting to women ages 18 years and older for breast cancer-related pain. The majority of the sample were ages 46 to 64 years (60.5%), Nonwhite (75.2%), publicly insured (66.2%), and with nonmetastatic disease (86.1%). Almost one-fifth (19.6%) of the prescriptions were written to current smokers, 21.3% to former smokers, and 58.1% to nonsmokers. Nonsmoking status predicted an increased odds of receiving a prescription ≥ 50 MME (odds ratio [OR] = 1.98, 95% confidence interval [CI]: 1.08-3.60, P = 0.030) and ≥ 90 MME (OR = 6.29, 95% CI: 1.38-28.58, P = 0.017) compared to current smokers. Nonsmoking status also predicted an increased odds of receiving a prescription ≥ 90 MME (OR = 4.29, 95% CI: 1.43-12.92, P = 0.009) compared to former smokers. LIMITATIONS: This cross-sectional sample was drawn from a single institution and only included the breast cancer population and may not be generalizable to other populations or institutions. Second, our sample was drawn from secondary data not collected for the purposes of our study. This limits the inclusion of other variables that may impact the opioid-prescribing behaviors of oncologists, potentially resulting in bias. CONCLUSIONS: During a time of heightened awareness of opioid-related harm, as well as implementation of national opioid-prescribing guidelines, current smoking may potentially be impacting how oncologists evaluate the need for opioids to treat breast cancer-related pain. Further studies that examine the relationship between smoking status, perceived need for opioids, and evaluative need for opioids in cancer populations are warranted. KEY WORDS: Cancer pain, opioids, smoking, breast cancer, opioid-prescribing guidelines, health policy, oncology, end of life.

Continuity of opioid prescribing among older adults on long-term opioids.

OBJECTIVES: To describe the continuity of opioid prescribing and prescriber characteristics among older adults with chronic noncancer pain (CNCP) who are on long-term opioid therapy (LTOT) and to evaluate the association of continuity of opioid prescribing and prescriber characteristics with the risk of opioid-related adverse events. STUDY DESIGN: Nested case-control design. METHODS: This study employed a nested case-control design using a 5% random sample of the national Medicare administrative claims data for 2012-2016. Eligible individuals experiencing a composite outcome of opioid-related adverse events were defined as cases and matched to controls using incidence density sampling. Continuity of opioid prescribing (operationalized using the Continuity of Care Index) and prescriber specialty were assessed among all eligible individuals. Conditional logistic regression was conducted to assess the relationships of interest after accounting for known confounders. RESULTS: Individuals with low (odds ratio [OR], 1.45; 95% CI, 1.08-1.94) and medium (OR, 1.37; 95% CI, 1.04-1.79) continuity of opioid prescribing were found to have greater odds of experiencing a composite outcome of opioid-related adverse events compared with individuals with high prescribing continuity. Fewer than 1 in 10 (9.2%) older adults starting a new LTOT episode received at least 1 prescription from a pain specialist. Receiving a prescription from a pain specialist was not significantly associated with the outcome in adjusted analyses. CONCLUSIONS: We found that higher continuity of opioid prescribing, but not provider specialty, was significantly associated with fewer opioid-related adverse outcomes among older adults with CNCP.

Do Formulation and Dose of Long-Term Opioid Therapy Contribute to Risk of Adverse Events among Older Adults?

BACKGROUND: Chronic non-cancer pain (CNCP) is highly prevalent in older adults and long-term opioid therapy (LTOT) has been used to manage chronic pain. However, the safety of LTOT among older adults with CNCP is not well-established and there is a need to identify therapy-related risk factors of opioid-related adverse events among older adults. OBJECTIVE: To evaluate the relationship between opioid dose and formulation and the risk of opioid-related adverse events among Medicare-eligible older adults on LTOT. DESIGN: Nested case-control study. PARTICIPANTS: Older Medicare beneficiaries (N=35,189) who received > 3 opioid prescriptions with a total days-supply of >45 days within a 90-day period for CNCP between 2012 and 2016. MAIN MEASURES: This study utilized Medicare 5% medical and prescription claims data. Outcome measures included opioid-induced respiratory depression (OIRD), opioid overdose, all-cause mortality, and a composite outcome, defined as the first occurrence of any of the previous three events. Key independent variables were opioid formulation and opioid dose (measured in morphine milligram equivalents (MME)) prescribed during LTOT. KEY RESULTS: Seventy-four OIRD, 133 overdose, 982 all-cause mortality, and 1122 composite outcome events were observed during follow-up. In unadjusted analyses, the use of combination opioids (OR: 4.52 [95%CI: 1.51-13.47]) was significantly associated with OIRD compared to short-acting (SA) opioids. In adjusted analyses, opioid-related adverse events were significantly associated with the use of LA (overdose OR: 13.00 [95%CI: 1.30-130.16] and combination opioids (overdose OR: 6.27 [95%CI: 1.91-20.55]; mortality OR: 2.75 [95%CI: 1.87-4.04]; composite OR: 2.82 [95%CI: 2.01-3.96]) when compared to SA opioids. When compared to an average dose of less than 20 MME, outcomes were significantly associated with doses of 20-50 MME (mortality OR: 1.61 [95%CI: 1.24-2.10]; composite OR: 1.59 [95%CI: 1.26-2.01]) and >50 MME (mortality OR: 1.99 [95%CI: 1.28-3.10]; composite OR: 2.09 [95%CI: 1.43-3.04]). CONCLUSIONS: Older adults receiving medically prescribed opioids at higher doses and those using LA and combination of LA and SA opioids are at increased risks for opioid-related adverse events, highlighting the need for close patient supervision.

Patterns of Long-Term Prescription Opioid Use Among Older Adults in the United States: A Study of Medicare Administrative Claims Data.

BACKGROUND: Long-term opioid therapy was prescribed with increasing frequency over the past decade. However, factors surrounding long-term use of opioids in older adults remains poorly understood, probably because older people are not at the center stage of the national opioid crisis. OBJECTIVES: To estimate the annual utilization and trends in long-term opioid use among older adults in the United States. STUDY DESIGN: Retrospective cohort study. SETTING: Data from Medicare-enrolled older adults. METHODS: This study utilized a nationally representative sample of Medicare administrative claims data from the years 2012 to 2016 containing records of health care services for more than 2.3 million Medicare beneficiaries each year. Medicare beneficiaries who were 65 years of age or older and who were enrolled in Medicare Parts A, B, and D, but not Part C, for at least 10 months in a year were included in the study. We measured annual utilization and trends in new long-term opioid use episodes over 4 years (2013-2016). We examined claims records for the demographic characteristics of the eligible individuals and for the presence of chronic non-cancer pain (CNCP), cancer, and other comorbidities. RESULTS: From 2013 to 2016, administrative claims of approximately 2.3 million elderly Medicare beneficiaries were analyzed in each year with a majority of them being women (~56%) and white (~82%) with a mean age of approximately 75 years. The proportion of all eligible beneficiaries with at least one new opioid prescription increased from 6.64% in 2013, peaked at 10.32% in 2015, and then decreased to 8.14% in 2016. The proportion of individuals with long-term opioid use among those with a new opioid prescription was 12.40% in 2013 and 10.20% in 2016. Among new long-term opioid users, the proportion of beneficiaries with a cancer diagnosis during the study years increased from 13.30% in 2013 to 15.67% in 2016, and the proportion with CNCP decreased from 30.25% in 2013 to 27.36% in 2016. Across all years, long-term opioid use was consistently high in the Southern states followed by the Midwest region. LIMITATIONS: This study used Medicare fee-for-service administrative claims data to capture prescription fill patterns, which do not allow for the capture of individuals enrolled in Medicare Advantage plans, cash prescriptions, or for the evaluation of appropriateness of prescribing, or the actual use of medication. This study only examined long-term use episodes among patients who were defined as opioid-naive. Finally, estimates captured for 2016 could only utilize data from 9 months of the year to capture 90-day long-term-use episodes. CONCLUSIONS: Using a national sample of elderly Medicare beneficiaries, we observed that from 2013 to 2016 the use of new prescription opioids increased from 2013 to 2014 and peaked in 2015. The use of new long-term prescription opioids peaked in 2014 and started to decrease from 2015 and 2016. Future research needs to evaluate the impact of the changes in new and long-term prescription opioid use on population health outcomes.

Backstories on the US Opioid Epidemic. Good Intentions Gone Bad, an Industry Gone Rogue, and Watch Dogs Gone to Sleep.

Epidemics of opioid use are old news in the United States, but an epidemic that kills over 200,000 Americans is not. A multiplicity of intertwined factors have brought us to this place. From 30,000 feet, it is the story of good intentions gone bad, a drug industry gone rogue, and government watch dog agencies gone to sleep. At ground level, it is the story of physicians unfamiliar with addictive drugs and drug addiction, new long-acting opioids deceptively marketed, cheap black tar heroin, encouragement to use opioids for chronic noncancer pain by professional organizations with conflicts of interest and without science, a culture intolerant to pain and tolerant to drug use, and the greedy response of the pharmaceutical industry and drug cartels to an expanding market opportunity. These factors are among those that have joined to form a tsunami of addiction and deaths that keeps on coming. A better understanding of them could speed the end of the present cycle of opioid abuse, perhaps prevent others, and inform future decisions about pain management.

Extreme Ends of Pain Sensitivity in SCN9A Mutation Variants: Case Report and Literature Review.

Pain insensitivity disorders are rare; however, when individuals are insensitive to pain, they are significantly more vulnerable to physical injuries, with higher morbidity and mortality rates, compared with the general population. The authors present the case of an 11-month-old male infant with SCN 9A gene mutation that resulted in congenital insensitivity to pain, while his mother, with a different mutation of the same gene, had hypersensitivity to pain. This is a rare familial presentation of the extreme ends of pain sensitivity, and might be the first such example in medical literature. There is little available information regarding the treatment of pain insensitivity disorders. The authors provide a brief discussion regarding diagnosis (including differentials), known etiology, and treatment of congenital insensitivity to pain, of which a multidisciplinary treatment approach is recommended.

Spinal epidural hematoma following a thoracic epidural in a child with sickle cell disease.

Acute liver dysfunction in the perioperative period may increase the risk of epidural hematoma in a patient with a neuraxial catheter. Coagulation testing needs to be carefully monitored in these patients. An epidural hematoma should be ruled out urgently by CT or MRI in cases of a persistent motor block.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN): could retinoids play a causative role?

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are overlapping manifestations on a spectrum of acute drug-induced conditions associated with severe blistering, skin peeling, and multi-organ damage. TEN is an eruption resembling severe scalding, with ≥30% skin detachment. SJS is a mild form of TEN, characterized histologically by epidermal keratinocyte apoptosis with dermo-epidermal separation and extensive small blisters with <10% body surface skin detachment. The syndrome can be induced by numerous medications and typically occurs 1-4 weeks after the initiation of therapy. Granulysin is found in the lesions of patients with SJS/TEN and plays a significant pathogenic role in the condition, but the overall mechanisms linking medications, granulysin, and disease manifestations remain obscure. This paper reviews evidence suggesting that the different medications implicated in SJS/TEN have the common property of interacting and synergizing with endogenous retinoids (vitamin A and its congeners), in many instances causing the latter to accumulate in and damage the liver, the main storage organ for vitamin A. It is hypothesized that liver damage leads to the spillage of toxic retinoid compounds into the circulation, resulting in an endogenous form of hypervitaminosis A and cytotoxicity with widespread apoptosis, mediated by granulysin and recognized as SJS/TEN. Subject to testing, the model suggests that symptom worsening could be arrested at onset by lowering the concentration of circulating retinoids and/or granulysin via phlebotomy or plasmapheresis or by pharmacological measures to limit their expression.

Pain control in sickle cell disease patients: use of complementary and alternative medicine.

OBJECTIVE: To examine the factors associated with the use of complementary and alternative medicine (CAM) as reported by patients attending an adult sickle cell clinic at a tertiary institution. DESIGN: Cross-sectional survey. SETTING: This study was conducted in a university tertiary care adult sickle cell clinic. SUBJECTS: Adult sickle cell patients. METHOD: Following Institutional Review Board approval, a questionnaire was administered to patients in a sickle cell clinic to examine their use of CAM for managing pain at home and while admitted to the hospital. RESULTS: Of the 227 respondents who completed the questionnaire, 92% experienced pain lasting from 6 months to more than 2 years. Two hundred and eight (91.6%) indicated that they have used CAM within the last 6 months to control pain. The frequency of CAMs use was higher among females, singles, those with more education, and higher household income. CONCLUSIONS: This study shows that a substantial majority of sickle cell patients live with pain on a regular basis and that there is substantial CAM use in the adult Sickle cell disease population. Being female and having a high school or higher education were significantly correlated with the use of CAM in sickle cell patients. A variety of CAM therapies are used, with the most common being prayer.

American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I--evidence assessment.

BACKGROUND: Opioid abuse has continued to increase at an alarming rate since the 1990 s. As documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration, available evidence suggests a wide variance in chronic opioid therapy of 90 days or longer in chronic non-cancer pain. Part 1 describes evidence assessment. OBJECTIVES: The objectives of opioid guidelines as issued by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to produce consistency in the application of an opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. The focus of these guidelines is to curtail the abuse of opioids without jeopardizing non-cancer pain management with opioids. RESULTS: 1) There is good evidence that non-medical use of opioids is extensive; one-third of chronic pain patients may not use prescribed opioids as prescribed or may abuse them, and illicit drug use is significantly higher in these patients. 2) There is good evidence that opioid prescriptions are increasing rapidly, as the majority of prescriptions are from non-pain physicians, many patients are on long-acting opioids, and many patients are provided with combinations of long-acting and short-acting opioids. 3) There is good evidence that the increased supply of opioids, use of high dose opioids, doctor shoppers, and patients with multiple comorbid factors contribute to the majority of the fatalities. 4) There is fair evidence that long-acting opioids and a combination of long-acting and short-acting opioids contribute to increasing fatalities and that even low-doses of 40 mg or 50 mg of daily morphine equivalent doses may be responsible for emergency room admissions with overdoses and deaths. 5) There is good evidence that approximately 60% of fatalities originate from opioids prescribed within the guidelines, with approximately 40% of fatalities occurring in 10% of drug abusers. 6) The short-term effectiveness of opioids is fair, whereas the long-term effectiveness of opioids is limited due to a lack of long-term (> 3 months) high quality studies, with fair evidence with no significant difference between long-acting and short-acting opioids. 7) Among the individual drugs, most opioids have fair evidence for short-term and limited evidence for long-term due to a lack of quality studies. 8) The evidence for the effectiveness and safety of chronic opioid therapy in the elderly for chronic non-cancer pain is fair for short-term and limited for long-term due to lack of high quality studies; limited in children and adolescents and patients with comorbid psychological disorders due to lack of quality studies; and the evidence is poor in pregnant women. 9) There is limited evidence for reliability and accuracy of screening tests for opioid abuse due to lack of high quality studies. 10) There is fair evidence to support the identification of patients who are non-compliant or abusing prescription drugs or illicit drugs through urine drug testing and prescription drug monitoring programs, both of which can reduce prescription drug abuse or doctor shopping. DISCLAIMER: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance.

RESULTS: Part 2 of the guidelines on responsible opioid prescribing provides the following recommendations for initiating and maintaining chronic opioid therapy of 90 days or longer. 1. A) Comprehensive assessment and documentation is recommended before initiating opioid therapy, including documentation of comprehensive history, general medical condition, psychosocial history, psychiatric status, and substance use history. ( EVIDENCE: good) B) Despite limited evidence for reliability and accuracy, screening for opioid use is recommended, as it will identify opioid abusers and reduce opioid abuse. ( EVIDENCE: limited) C) Prescription monitoring programs must be implemented, as they provide data on patterns of prescription usage, reduce prescription drug abuse or doctor shopping. ( EVIDENCE: good to fair) D) Urine drug testing (UDT) must be implemented from initiation along with subsequent adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. ( EVIDENCE: good) 2. A) Establish appropriate physical diagnosis and psychological diagnosis if available prior to initiating opioid therapy. ( EVIDENCE: good) B) Caution must be exercised in ordering various imaging and other evaluations, interpretation and communication with the patient, to avoid increased fear, activity restriction, requests for increased opioids, and maladaptive behaviors. ( EVIDENCE: good) C) Stratify patients into one of the 3 risk categories - low, medium, or high risk. D) A pain management consultation, may assist non-pain physicians, if high-dose opioid therapy is utilized. ( EVIDENCE: fair) 3. Essential to establish medical necessity prior to initiation or maintenance of opioid therapy. ( EVIDENCE: good) 4. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. ( EVIDENCE: good) 5. A) Long-acting opioids in high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids, as there is no significant difference between long-acting and short-acting opioids for their effectiveness or adverse effects. ( EVIDENCE: fair) B) The relative and absolute contraindications to opioid use in chronic non-cancer pain must be evaluated including respiratory instability, acute psychiatric instability, uncontrolled suicide risk, active or history of alcohol or substance abuse, confirmed allergy to opioid agents, coadministration of drugs capable of inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of controlled substances, and concomitant use of heavy doses of central nervous system depressants. ( EVIDENCE: fair to limited) 6. A robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion. ( EVIDENCE: fair) 7. A) Once medical necessity is established, opioid therapy may be initiated with low doses and short-acting drugs with appropriate monitoring to provide effective relief and avoid side effects. ( EVIDENCE: fair for short-term effectiveness, limited for long-term effectiveness) B) Up to 40 mg of morphine equivalent is considered as low dose, 41 to 90 mg of morphine equivalent as a moderate dose, and greater than 91 mg of morphine equivalence as high dose. ( EVIDENCE: fair) C) In reference to long-acting opioids, titration must be carried out with caution and overdose and misuse must be avoided. ( EVIDENCE: good) 8. A) Methadone is recommended for use in late stages after failure of other opioid therapy and only by clinicians with specific training in the risks and uses. ( EVIDENCE: limited) B) Monitoring recommendation for methadone prescription is that an electrocardiogram should be obtained prior to initiation, at 30 days and yearly thereafter. ( EVIDENCE: fair) 9. In order to reduce prescription drug abuse and doctor shopping, adherence monitoring by UDT and PMDPs provide evidence that is essential to the identification of those patients who are non-compliant or abusing prescription drugs or illicit drugs. ( EVIDENCE: fair) 10. Constipation must be closely monitored and a bowel regimen be initiated as soon as deemed necessary. ( EVIDENCE: good) 11. Chronic opioid therapy may be continued, with continuous adherence monitoring, in well-selected populations, in conjunction with or after failure of other modalities of treatments with improvement in physical and functional status and minimal adverse effects. ( EVIDENCE: fair). DISCLAIMER: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain.

BACKGROUND: Even though opioids have been used for pain for thousands of years, opioid therapy for chronic non-cancer pain is controversial due to concerns regarding the long-term effectiveness and safety, particularly the risk of tolerance, dependance, or abuse. While the debate continues, the use of chronic opioid therapy for chronic non-cancer pain has increased exponentially. Even though evidence is limited, multiple expert panels have concluded that chronic opioid therapy can be effective therapy for carefully selected and monitored patients with chronic non-cancer pain. STUDY DESIGN: A systematic review of randomized trials of opioid management for chronic non-cancer pain. OBJECTIVE: The objective of this systematic review is to evaluate the clinical efficacy of opioids in the treatment of chronic non-cancer pain. METHODS: A comprehensive evaluation of the literature relating to opioids in chronic non-cancer pain was performed. The literature was evaluated according to Cochrane review criteria for randomized controlled trials (RCTs) and Jadad criteria. A literature search was conducted by using PubMed, EMBASE, Cochrane library, ECRI Institute Library, U.S. Food and Drug Administration (FDA) website, U.S. National Guideline Clearinghouse (NGC), Database of Abstracts of Reviews of Effectiveness (DARE), clinical trials, systematic reviews and cross references from systematic reviews. The level of evidence was classified as good, fair, or poor based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF) and used by other systematic reviews and guidelines. OUTCOME MEASURES: Pain relief was the primary outcome measure. Other outcome measures were functional improvement, withdrawals, and adverse effects. RESULTS: Based on the USPSTF criteria, the indicated level of evidence was fair for Tramadol in managing osteoarthritis. For all the drugs assessed, including Tramadol, for all other conditions, the evidence was poor based on either weak positive evidence, indeterminate evidence, or negative evidence. LIMITATIONS: A paucity of literature, specifically with follow-up beyond 12 weeks for all types of opioids with controlled trials for various chronic non-cancer pain conditions. CONCLUSIONS: This systematic review illustrated fair evidence for Tramadol in managing osteoarthritis with poor evidence for all other drugs and conditions. Thus, recommendations must be based on non-randomized studies.