Importance Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose. Objective To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care. Process The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category. Evidence Synthesis Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects. Recommendations There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone. Conclusions and Relevance The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.

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CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016

/pdf/cdc-guideline-for-prescribing-opioids-for-chronic-pain-48d7kdjqlr.pdf

CDC guideline for prescribing opioids for chronic pain

This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025) as well as a website (http://www.cdc.gov/drugoverdose/prescribingresources.html) with additional tools to guide clinicians in implementing the recommendations.

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CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures.

2. A number of treatment options exist for symptomatic diabetic neuropathy.

3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.

4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies.

View this table:

Table 1 
Classification for diabetic neuropathies



Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms.

This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …

/pdf/diabetic-neuropathy-a-position-statement-by-the-american-2213pwegte.pdf

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

Painful diabetic peripheral neuropathy (DPN) may not be adequately managed with available therapeutic options. This phase III, randomized-withdrawal, placebo-controlled trial evaluated the safety a...

Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial

Background: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain.

Methods:  Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study.

Results:  A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients.

Conclusion:  Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.

Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.

502 patient global impression of change associated with tapentadol prolonged release (pr) for the management of painful diabetic peripheral neuropathy (dpn)

Background Caffeine enhances the efficacy of non-opioid analgesics. Data on the cardiovascular health effects of caffeine intake are controversial, and studies on the cardiovascular effects of medical caffeine use are lacking. Objective The study aims to explore the cardiovascular effects of an ibuprofen/caffeine combination in comparison to ibuprofen alone. Methods Secondary analysis of a previously reported bioequivalence study of a single dose of a fixed dose ibuprofen/caffeine combination (400/100 mg) vs. ibuprofen alone in a randomized, cross-over design in 36 healthy volunteers. Plasma catecholamines were analyzed to enhance mechanistic interpretation of the data. Results After exclusion of 10 protocol violators (pre-dosing intake of caffeine), vital signs were comparable over a 24-h period in the absence and presence of caffeine. Plasma catecholamine levels were also comparable. Conclusion These data do not support the hypothesis that occasional intake of a small dose of caffeine as part of pain medication imposes a health risk due to vital sign changes. Based on the proven increase in efficacy, the addition of caffeine to non-opioid analgesics such as IBU has a favorable risk/benefit profile for occasional use.

https://doi.org/10.2174/1574886317666220414125027

Lack of Evidence for Blood Pressure Effects of Caffeine Added to Ibuprofen

Potential habituation could be a safety concern associated with the long-term use of bisacodyl in patients with constipation. In this study, we evaluated whether patients with constipation who require long-term treatment with bisacodyl will remain on a stable dose when treated for ≥ 28 days. In this retrospective, population-based, observational cohort study, electronic medical record data of adult patients with constipation between January 1, 2011, and December 31, 2019, were collected from The Health Improvement Network French database. Total bisacodyl exposure during the long-term (≥ 28 days) and follow-up (12 months) periods was evaluated. The primary endpoint was the dose change status of bisacodyl during the follow-up period from the initial dose in the long-term cohort. Out of 5725 bisacodyl users in the database, 218 patients qualified to be part of the long-term cohort. A total of 166 (76.1%), 37 (17%), and 15 (6.9%) patients were initiated on bisacodyl at 5, 7.5, and 10 mg, respectively. During the follow-up, most (94%) of the patients remained on the same dose as initially prescribed for the first year. In contrast, only seven (3.2%) patients had their dose increased (from the initial prescribed dose of 5 mg), and the remaining six (2.8%) patients decreased their dose (four patients from the 7.5 mg group and two from the 10 mg group). Bisacodyl can be prescribed at a stable dose for > 28 days as most patients remained on their initial prescribed dose during the follow-up period. No signs of habituation were observed in this real-world study. 

https://link.springer.com/content/pdf/10.1007/s40801-023-00354-6.pdf

A Retrospective Real-World Observational Study Assessing the Evolution of Bisacodyl Prescriptions in Patients with Constipation During Long-Term Treatment

Robert Lange

Papers

Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial

Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.

502 patient global impression of change associated with tapentadol prolonged release (pr) for the management of painful diabetic peripheral neuropathy (dpn)

Lack of Evidence for Blood Pressure Effects of Caffeine Added to Ibuprofen

A Retrospective Real-World Observational Study Assessing the Evolution of Bisacodyl Prescriptions in Patients with Constipation During Long-Term Treatment