Research Gaps on Use of Opioids for Chronic Noncancer Pain: Findings From a Review of the Evidence for an American Pain Society and American Academy of Pain Medicine Clinical Practice Guideline

Chronic noncancer pain is common and use of opioids is increasing. Previously published guidelines on use of opioids for chronic noncancer pain have been based primarily on expert consensus due to lack of strong evidence. We conducted searches on Ovid MEDLINE and the Cochrane databases through July 2008 to identify studies that addressed one or more of 37 Key Questions that a multidisciplinary expert panel identified as important to be answered to generate evidence-based recommendations on the use of opioids for chronic noncancer pain. A total of 14 systematic reviews, 38 randomized trials not included in a previously published systematic review, and 13 other studies met inclusion criteria. Almost all of the randomized trials of opioids for chronic noncancer pain were short-term efficacy studies. Critical research gaps on use of opioids for chronic noncancer pain include: lack of effectiveness studies on long-term benefits and harms of opioids (including drug abuse, addiction, and diversion); insufficient evidence to draw strong conclusions about optimal approaches to risk stratification, monitoring, or initiation and titration of opioid therapy; and lack of evidence on the utility of informed consent and opioid management plans, the utility of opioid rotation, the benefits and harms specific to methadone or higher doses of opioids, and treatment of patients with chronic noncancer pain at higher risk for drug abuse or misuse.PerspectiveCurrently, clinical decisions regarding the use of opioids for chronic noncancer pain need to be made based on weak evidence. Research funding priorities need to be set to address these critical research needs if the care of patients with chronic noncancer pain is to improve.     

Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain

Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related polices.PerspectiveSafe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel after a systematic review of the evidence.     

Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety

Opioid therapy for chronic noncancer pain (CNCP) is controversial due to concerns regarding long-term efficacy and adverse events (including addiction). We systematically reviewed the clinical evidence on patients treated with opioids for CNCP for at least six months. Of 115 studies identified by our search of eleven databases (through April 7, 2007), 17 studies (patients [n]=3,079) met inclusion criteria. Studies evaluated oral (studies [k]=7; n=1,504), transdermal (k=3; n=1, 993), and/or intrathecal (k=8; n=177) opioids. Many patients withdrew from the clinical trials due to adverse effects (oral: 32.5% [95% confidence interval (CI), 26.1%-39.6%]; intrathecal: 6.3% [95% CI, 2.9%-13.1%]; transdermal: 17.5% [95% CI, 6.5%-39.0%]), or due to insufficient pain relief (oral: 11.9% [95% CI, 7.8%-17.7%]; intrathecal: 10.5% [95% CI, 3.5%-27.4%]; transdermal: 5.8% [95% CI, 4.2%-7.3%]). Signs of opioid addiction were reported in only 0.05% (1/2,042) of patients and abuse in only 0.43% (3/685). There was an insufficient amount of data on transdermal opioids to quantify pain relief. For patients able to remain on oral or intrathecal opioids for at least six months, pain scores were reduced long-term (oral: standardized mean difference [SMD] 1.99, 95% CI, 1.17-2.80; intrathecal: SMD 1.33, 95% CI, 0.97-1.69). We conclude that many patients discontinue long-term opioid therapy due to adverse events or insufficient pain relief; however, weak evidence suggests that oral and intrathecal opioids reduce pain long-term in the relatively small proportion of individuals with CNCP who continue treatment.     

Patterns of opioid use for chronic noncancer pain in the Veterans Health Administration from 2009 to 2011

Although opioids are frequently prescribed for chronic noncancer pain (CNCP) among Veterans Health Administration (VHA) patients, little has been reported on national opioid prescribing patterns in the VHA. Our objective was to better characterize the dosing and duration of opioid therapy for CNCP in the VHA. We analyzed national VHA administrative and pharmacy data for fiscal years 2009 to 2011. For individuals with CNCP diagnoses and any opioid use in the fiscal year, we calculated the distribution of individual mean daily opioid dose, individual total days covered with opioids in a year, and individual total opioid dose in a year. We also investigated the factors associated with being in the top 5% of individuals for total opioid dose in a year, which we term receipt of high-volume opioids. About half of the patients with CNCP received opioids in a given fiscal year. The median daily dose was 21 mg morphine equivalents. Approximately 4.5% had a mean daily dose higher than 120 mg morphine equivalents. The median days covered in a year was 115 to 120 days in these years for those receiving opioids. Fifty-seven percent had at least 90 days covered with opioids per year. Major depression and posttraumatic stress disorder were positively associated with receiving high-volume opioids, but nonopioid substance use disorders were not. Among VHA patients with CNCP, chronic opioid therapy occurs frequently, but for most patients, the average daily dose is modest. Doses and duration of therapy were unchanged from 2009 to 2011.     

Continuous opioid therapy (COT) is rarely advisable for refractory chronic daily headache: limited efficacy, risks, and proposed guidelines

Intractable pain, headache or otherwise, is a devastating and life-controlling experience. The need to effectively and aggressively control pain is a fundamental tenet of clinical care. In the past several years, increasing advocacy for continuous opioid therapy has become an important, if not controversial, theme in the development of treatment guidelines and teaching programs. Ironically, the increasing willingness of physicians to prescribe scheduled opioids for their headache and pain patients has occurred in the absence of compelling data demonstrating efficacy or long-term safety. To the contrary, two meta-analyses on chronic noncancer pain (CNCP) and one long-term uncontrolled study on headache patients demonstrate a relatively small number of patients benefiting from the treatment. Recent neuroscience data on the effects of opioids on the brain raise serious concern for long-term safety and also provide the basis for the mechanism by which chronic opioid use might induce progression of headache frequency and severity. Significant adverse effects, including influence on sexual hormonal balances, physical and psychological dependence, the development of opioid-induced hyperalgesia, and cardiac arrhythmia and sudden death that can be seen with standard dosages of methadone, make a strong argument against widespread use of continuous opioid therapy (COT) in otherwise healthy young and middle-aged headache patients.
We believe that COT should be used in rare circumstances for chronic headache patients, and propose initial guidelines for selecting patients and monitoring treatment. The physician should be well versed in the details of opioid prescribing, administration, and monitoring, and should be prepared to discontinue opioids when clinical justification, patient behavior, or failure to achieve therapeutic goals make discontinuance necessary.     

Problems and concerns of patients receiving chronic opioid therapy for chronic non-cancer pain

The value of chronic opioid therapy (COT) for chronic non-cancer pain (CNCP) patients is determined by a balance of poorly understood benefits and harms. Traditionally, this balance has been framed as the potential for improved pain control versus risks of iatrogenic addiction, drug diversion, and aberrant drug-related behaviors. These potential harms are typically defined from the providers’ perspective. This paper seeks to clarify difficulties with the long-term use of opioids for CNCP from the patients’ perspective. We used the Prescribed Opioids Difficulties Scale (PODS) to assess current problems and concerns attributed to opioid use by 1144 adults receiving COT. Subjects were grouped into low (56.9%), medium (25.6%) and high (17.5%) PODS scorers. Among patients with high PODS scores, 64% were clinically depressed and 78% experienced high levels of pain-related interference with activities, compared to 28% depressed and 60% with high interference with activities among those with low PODS scores. High levels of opioid-related problems and concerns were not explained by differences in pain intensity or persistence. Patients with medium to high PODS scores were often concerned about their ability to control their use of opioid medications, but prior substance abuse diagnoses and receiving excess days supply of opioids were much less common in these patients than depression and pain-related interference with activities. These results suggest two types of potential harm from COT attributed by CNCP patients to opioids: psychosocial problems that are distinct from poor pain control and opioid control concerns that are distinct from opioid misuse or addiction.     

Opioid tolerance and dependence — do they matter?

The use of opioids has long been accepted as the standard of care in patients with cancer and acute pain. Opioids can further be used effectively in specific subgroups of patients with chronic nonmalignant pain states. While the development of tolerance and physical dependence are known effects of opioids in cancer and noncancer pain populations, these patients can not be regarded as addicted. However, long-term therapy with short-acting opioids predisposes to tolerance and addiction. Recent research has confirmed the important role of psychopathologic and psychosocial conditions as predictors of failed opioid effectiveness in a significant number of noncancer pain subgroups. The clinical picture of failed therapy may be complicated by noncompliance, concealed consumption of psychotropic substances, and diversion of prescribed opioids for various purposes as, e.g., selling for profit, or sharing excess opioids with others. This article discusses the effects of opioid therapy, including tolerance, physical dependence, drug-aberrant behavior, drug history, psychopathology, and somatization.     

Variable Use of Opioid Pharmacotherapy for Chronic Noncancer Pain in Europe: Causes and Consequences

ABSTRACT.?

According to the 2005 Pain in Europe Survey, the use of opioids to treat patients with chronic noncancer pain varies considerably among different countries in Europe. Undertreatment of chronic pain is common. This review examines the possible causes and consequences of limiting opioid availability to these patients. The causes of inadequate opioid use include medical, ethical, and cultural factors that influence prescribing decisions; legislative and health care system controls that serve to restrict the use of opioids for long-term treatment of non–cancer-related pain conditions; and poor treatment acceptance by patients. The validity of these restrictions is discussed in relation to the need to protect patients and society from harm due to adverse events, and the potential for misuse and abuse with prescribed opioids. This is balanced against the therapeutic goal of providing the best available pain-relieving treatment and to avoid the consequences of unnecessary suffering in patients with chronic noncancer pain.     

Do internal medicine residents find pain medication agreements useful?

BACKGROUND: Little is known about whether internal medicine residents find pain management agreements (PMAs) useful or whether PMA use is associated with more positive attitudes toward patients with chronic noncancer pain (CNCP). METHODS: We surveyed all internal medicine residents at Rhode Island Hospital regarding whether they found PMAs useful, what percentage of their patients taking chronic opioids had a signed PMA, and their attitudes toward and experiences with managing CNCP. RESULTS: Survey response rate was 89% (110/124). Ninety percent of respondents reported finding PMAs useful. A majority of respondents reported that PMAs were at least somewhat helpful for reducing multiple prescribers (76%), reducing requests for early refills (67%), reducing calls and pages from patients (57%), making it easier to discuss potential problems associated with chronic opioid use (73%), and making it easier to identify patients who are abusing pain medications (66%). Residents who reported greater use of PMAs reported a greater sense of preparation (r=0.20, P=0.04), greater confidence (r=0.18, P=0.06), and a greater sense of reward (r=0.24, P=0.02) for managing CNCP. In a multivariate analysis, PMA use was significantly associated with greater sense of preparation and greater sense of reward for managing CNCP. CONCLUSIONS: Among internal medicine residents, PMA use was associated with more positive attitudes toward CNCP management.     

Medikamentöse Therapie bei Rückenschmerzen

Today, a wide range of efficient analgesic and non-analgesic drugs for the treatment of back pain are available. However, drugs should never be the only mainstay of a back pain treatment program. Non-steroidal antiinflammatory drugs (NSAID) are widely used in acute back pain. NSAIDs prescribed at regular intervals are effective to reduce simple back pain. The different NSAIDs are effective for the reduction of this pain. They have serious adverse effects, particularly at high doses, in the elderly, and on long-term administration. The new cyclooxygenase II-inhibitors have less gastrointestinal complications. But the long-term experiences are limited up to now. Considerable controversy exists about the use of opioid analgesics in chronic noncancer pain. Many physicians are concerned about the effectiveness and adverse effects of opioids. Other clinicians argue that there is a role for opioid therapy in chronic noncancer pain, e. g. especially in chronic low back pain. There is a low incidence of organ toxicity in patients who respond to opioids. The incidence of abuse and addiction is likewise relatively low. The potential for increased function and improved quality of life seems to outweigh the risks. However, there is a lack of randomised controlled trials (RCT) on opioid therapy in a multimodal pain treatment approach. Clinical experience and some studies suggest administration of sustained release opioids because of better comfort for the patient and less risks for addiction. The opioids should be selected due to the specific side effects of the different drugs. For patients with pre-existing constipation transdermal fentanyl should be preferred. Antidepressant medications have been used for the treatment of chronic back pain, though there is only little scientific evidence for their effectiveness. There is no evidence for the use of antidepressants in acute low back pain. Trials of muscle relaxants for patients with acute back pain have used a wide range of agents, e. g. benzodiazepines. They mostly reduce acute back pain, but they have significant adverse effects including drowsiness and psychological and physical dependence even after relatively short treatment. Benzodiazepines are not indicated in the treatment of chronic back pain. Drugs are sometimes necessary for the patients to begin and persevere a multimodal treatment program. Drug therapy should be terminated as soon as other treatment strategies succeed. Unfortunately, no studies exist evaluating the place of analgesics within a multimodal treatment program.     

Bridging the Gap Between Mind and Body: A Biobehavioral Model of the Effects of Guided Imagery on Pain,Pain Disability,and Depression

Chronic noncancer pain (CNCP) is a common and complex disorder associated with declines in physical health and functional status, emotional well-being, and quality of life. To best address the complexity of this condition, research and clinical practice for CNCP should be guided by a framework incorporating both biologic and psychologic factors. This article presents a biobehavioral model of chronic pain that hypothesizes mechanisms related to the effectiveness of a complementary therapy, guided imagery (GI), for this population. Using the research-to-model/theory strategy, we mapped findings from published reports of interdisciplinary research into physiologic and psychologic aspects of the nature and mechanisms of pain, as well as the use of GI for pain, to build the model of GI's effects on pain, pain disability, and depression. In the model, these outcomes of GI for persons experiencing CNCP are mediated by psychologic (pain self-efficacy and pain beliefs) and physiologic (immune-mediated analgesia and sickness response) variables. A biobehavioral approach to nursing phenomena will advance understanding of health and health-related issues and has the potential to improve outcomes through delineation of mechanisms underlying relationships between psychologic and biologic factors. Increased consumer use of complementary therapies to treat pain, the current cost-driven health care system, and the mandate for evidence-based practice support the need to validate the efficacy of such therapies. This empirically derived model provides a framework for practice and research for nurses and other health care providers to promote health, function, and well-being in persons with CNCP.     

Sex hormone suppression by intrathecal opioids: a prospective study

OBJECTIVE: Sexual dysfunction and low testosterone levels have been observed previously in males with chronic noncancer pain treated with intrathecal opioids. To investigate the hypothesis that intrathecal opioids suppress the hypothalamic-pituitary-gonadal axis, a prospective nonrandomized investigation of the function of this axis was undertaken. DESIGN: Ten males with chronic noncancer pain were evaluated for clinical and biochemical evidence of hypogonadism at baseline and during the first twelve weeks of intrathecal opioid therapy. RESULTS: Intrathecal opioid administration resulted in a significant (p <0.0001) reduction in serum testosterone, from 7.7 +/- 1.1 (mean +/- SEM) nmol/L at baseline to 2.0 +/- 0.7, 2.8 +/- 0.5, and 4.0 +/- 0.9 nmol/L at 1, 4, and 12 weeks, respectively. This was associated with a reduction in libido and potency. Luteinizing hormone and follicle-stimulating hormone levels remained within reference ranges, indicating central rather than peripheral suppression. CONCLUSIONS: Administration of intrathecal opioids may result in hypogonadotrophic hypogonadism. As part of the consent for therapy process, patients should be informed about this effect and its management. With long-term intrathecal opioid administration, the hypothalamic-pituitary-gonadal axis should be monitored. Where indicated, testosterone replacement should be undertaken to improve sexual function and prevent the potential metabolic effects of hypogonadism, in particular, osteoporosis.