Opioids For Management Of Chronic Pain Research Articles

6.1 Molecular Pharmacology of Opioids: Chronic Stress and Developmental Exposures

This talk will review opioid receptor neuroscience as it pertains to adolescents and neonatal opioid exposure, as well as system effects from chronic stress. We are currently in the midst of an epidemic of opioid misuse. Efforts to address this crisis involve recognizing the neurobiological risk factors of substance use disorders, understanding alternatives to opioids for chronic pain management, and developing safer opioid medications.

A Shared Medical Appointment on the Benefits and Risks of Opioids in Chronic Pain Management: Evaluation of a Pilot Program in an Ambulatory Setting

A Shared Medical Appointment on the Benefits and Risks of Opioids in Chronic Pain Management: Evaluation of a Pilot Program in an Ambulatory Setting

An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US.

Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%–10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of μ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP.

Discrepancies Between Perceived Benefit of Opioids and Self-Reported Patient Outcomes.

ObjectiveThere is little empirical evidence supporting the long-term use of opioid therapy for chronic pain, suggesting the need to reevaluate the role of opioids in chronic pain management. Few studies have considered opioid use and opioid cessation from the perspective of the patient.MethodsThis prospective structured interview study included 150 new patients seeking treatment for chronic pain at an outpatient tertiary care pain clinic.ResultsOf the 150 patients, 56% (N = 84) reported current opioid use. Opioids users reported higher pain severity (t(137) = -3.75, P < 0.001), worse physical functioning (t(136) = -3.82, P < 0.001), and more symptoms of depression (t(136) = -1.98, P = 0.050) than nonusers. Among opioid users, 45.6% reported high pain (>7), 60.8% reported low functioning (>7), and 71.4% reported less than a 30% reduction in pain severity since starting opioids, suggesting that many patients are unlikely to be receiving adequate benefit. Overall, 66.3% of current opioid users reported moderate to high opioid-related difficulties on the prescribed opioids difficulties scale, and patients with depression were more likely to report greater difficulties. There was no association between helpfulness of opioids over the past month and opioid-related difficulties (r(75) = -0.07, P = 0.559), current pain severity (r(72)=0.05, P = 0.705), or current pain interference (r(72) = 0.20, P = 0.095).ConclusionsDespite clinical indicators that question the benefit, patients may continue to report that their opioids are helpful. Such discrepancies in patients’ perceptions will likely pose significant barriers for implementing opioid cessation guidelines in clinical practice.

A Role for Opioids in Chronic Pain Management

A Role for Opioids in Chronic Pain Management

A Role for Opioids in Chronic Pain Management—Reply

A Role for Opioids in Chronic Pain Management—Reply

CXCR4 signaling mediates morphine-induced tactile hyperalgesia

Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulfate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C–C chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) in a line of F11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel approach to the management of the side effects associated with the use of opioids for chronic pain management.

Preliminary Study of the Plasma and Cerebrospinal Fluid Concentrations of IL-6 and IL-10 in Patients with Chronic Pain Receiving Intrathecal Opioid Infusions by Chronically Implanted Pump for Pain Management

This preliminary study assessed possible relationships between plasma and/or cerebrospinal fluid (CSF) concentrations of the pleiotropic cytokine, interleukin (IL)-6, the anti-inflammatory cytokine, IL-10, and levels of pain reported by patients receiving intrathecal (i.t.) opioids. A prospective study quantifying IL-6 and IL-10 concentrations using enzyme-linked immunoassays in samples of plasma and CSF as well as assessment of pain scores in patients receiving intrathecal opioids for management of chronic noncancer pain. Outpatient pain clinics. Patients with chronic pain receiving intrathecal morphine or hydromorphone alone or in combination with local anesthetics. Two groups of patients were studied. The first group (n = 50) had been receiving long-term i.t. opioids by chronically implanted pump for approximately 5 years; paired samples of plasma and CSF were collected at the time of i.t. pump refill. For the second patient group (n = 10), possible temporal changes in the plasma and/or CSF concentrations of IL-6 and IL-10 were investigated for 3 months after initiation of i.t. opioid infusions. For patients receiving long-term i.t. opioid infusions, there were significant inverse correlations (P < or = 0.05) between pain intensity and the plasma (but not CSF) IL-10 and IL-6 concentrations. Despite the considerable inter-patient variability in the CSF concentrations of IL-6 in the long-term cohort, the mean CSF IL-6 concentration was approximately fivefold higher in patients receiving long-term i.t. opioids relative to those receiving i.t. opioids for only 3 months. The significant inverse correlations observed between pain intensity and the plasma IL-6 and IL-10 concentrations in patients receiving longterm i.t. opioids for chronic pain management, suggests that these cytokines are worthy of further investigation as possible biomarkers of persistent pain.

A Comparison of Common Screening Methods for Predicting Aberrant Drug-Related Behavior among Patients Receiving Opioids for Chronic Pain Management

The ability to predict risk for violating opioid medication policies, known as aberrant drug-related behavior, is critical for providing optimal treatment. Many pain management centers measure risk using one of several partially validated measures: the Screener and Opioid Assessment for Patients with Pain (SOAPP), the Diagnosis, Intractability, Risk, and Efficacy inventory (DIRE), and/or the Opioid Risk Tool (ORT). However, little is known about how these measures compare with each other in predicting aberrant drug-related behavior and discontinuance of opioid pain medications. The current study aimed to address this research question. Participants were 48 patients who attended a pain management center in Tennessee but were later discontinued from opioids for aberrant drug-related behavior. Patients referred for opioid medication for pain management participated in a semi-structured clinical interview with the staff psychologist and completed the aforementioned measures. Patients generally returned to the pain clinic on a monthly basis for medication management. Results. Analyses compared the sensitivity of each self-report measure and the clinical interview in predicting discontinuance for aberrant drug-related behavior. showed the highest sensitivity for the clinical interview (0.77) and the SOAPP (0.72), followed by the ORT (0.45) and the DIRE (0.17). Combining the clinical interview with the SOAPP increased sensitivity to 0.90. Among patients who were discontinued from opioids for aberrant drug-related behaviors, the clinical interview and the SOAPP were most effective at predicting risk at baseline. Implications for future research and clinical practice are discussed.

1307 CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of progression

Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulfate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C–C chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) in a line of F11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel approach to the management of the side effects associated with the use of opioids for chronic pain management.

Standard Therapy with Opioids in Chronic Pain Management

Moderate to severe pain is commonly experienced by cancer and non-cancer patients. Although opioids are generally the most important drugs in chronic pain management, their use in Italy remains low. We designed a prospective open trial to assess the efficacy and safety of a standard therapy clinically available for a large range of patients. A total of 172 consecutive patients (89 women and 83 men) with chronic pain (daily mean visual analogue scale (VAS) score > 4) that was not adequately managed by their existing pain regimen were enrolled to receive an immediate release (IR) dose of morphine: 30 mg/day (opioid-naive patients) or 60 mg/day (non-naive patients) for 5 days. After this period (start therapy), all patients were switched to slow release (SR) opioid therapy for 30 days (steady therapy). Each breakthrough pain (BTP) episode was treated with a single dose of IR morphine (20% of the daily dose) during all study periods. Daily VAS score was reduced from 7.4 +/- 1.3 at baseline to 3.8 +/- 1.5 (p < 0.0001) after 30 days of steady therapy in cancer and non-cancer patients. Fewer patients reported BTP events by study end (55% of patients with BTP at basal time had no BTP at last follow up), and the number of daily BTP events experienced by patients was reduced by therapy to 1-2 per day in 75% of patients reporting BTP. Further, the time delay to reach pain relief following administration of a rescue dose of IR morphine was 15 minutes or less in 52.1% of patients at study end. The standard therapy was well tolerated and fewer adverse effects were recorded at the end of the study period compared with baseline, with the exception of constipation, which showed a moderate increase (from 18.2% to 25.0%). Start therapy with IR morphine followed by conversion to SR opioid therapy could be implemented as a standard therapy to manage moderate to severe chronic pain in patients with cancer or non-cancer pain. ORamorph in TIBER study (ORTIBER).

Experience of Methadone Therapy in 100 Consecutive Chronic Pain Patients in a Multidisciplinary Pain Center

The objective of the study was to describe the experience of methadone use in 100 consecutive chronic pain patients managed in a single multidisciplinary center. A chart review of chronic pain patients on methadone therapy initiated at the Wasser Pain Management Center from January 2001 to June 2004. SETTING, PATIENTS, AND INTERVENTION: Outpatients receiving methadone for chronic pain management in a tertiary multidisciplinary pain center. Effects on pain relief and function, conversion ratio from other opioids, side effects, and disposition were reviewed. Charts of 100 methadone patients (age 45 +/- 11 years old; M/F: 3/7; duration of pain 129 +/- 110 months) managed by five physicians and one nurse were reviewed. The main reason for the initiation of methadone therapy was opioid rotation (72%). The average oral morphine equivalent dose was 77 mg/day before methadone therapy, and the methadone dose after initial stabilization was 42 mg with no consistent conversion ratio observed. The mean duration of methadone therapy was 11 months. Most of the patients (91%) were taking concomitant adjuvant analgesics or psychotropic agents, mostly antidepressants and anticonvulsants. The average Numeric Verbal Rating Score before and after methadone treatment was 7.2 +/- 1.7 and 5.2 +/- 2.5 (P < 0.0001). Thirty-five patients discontinued their methadone treatment mainly because of side effects, ineffectiveness, or both. From our experience, methadone is an effective alternative to conventional opioids for chronic pain management when used by experienced clinicians in a setting that allows for close monitoring and careful dose initiation and adjustment.

(891): An observational US survey (GI BURDEN) to characterize the burden of illness associated with opioid-induced bowel dysfunction and laxative use

While the benefits of opioids for chronic pain management are widely acknowledged, the frequency, severity and impact of associated gastrointestinal (GI) side effects remain poorly characterized. In the US, no therapy is approved to directly inhibit these side effects. Laxatives are used, but their utility may be limited, particularly over an extended time period. GI BURDEN (GastroIntestinal BUrden in patients Receiving opioids: Descriptive Evidence of unmet Need), a prospective cross-sectional and longitudinal observational survey, is currently underway in North America to assess the burden of illness resulting from opioid-induced bowel dysfunction (OBD) and laxative use. Patients (n=522) prescribed opioids for ≥30 days for chronic pain, experiencing constipation related to opioid use, and using a laxative on ≥2 days/week in the last 4 weeks were recruited to the 8-week observational phase of the study. Those enrolled completed QoL questionnaires at clinic visits, and recorded GI symptoms daily using an interactive voice response system. Interim analysis of 350 patients who have completed at least 4 weeks of observation revealed that, in spite of laxative use, over one-half of patients reported constipation on at least 50% of days. Symptoms of straining, false alarm, incomplete evacuation and hard/dry stools were reported by >50% of patients every week of the observation period. Beyond constipation, the most common GI symptoms were lower abdominal pain, bloating, and abdominal fullness, with 35-40% of patients reporting them as moderate–severe. The majority of patients (85–90%) reported cramping, bloating, and excessive gas associated with laxative treatment, with over a third considering these side effects moderate or severe. These interim data suggest opioid-treated chronic pain patients commonly experience GI symptoms, particularly constipation, despite regular laxative use. Laxatives themselves were also shown to be associated with undesirable GI side effects thus adding to the burden of illness for many patients.

Predictors of opioid misuse in patients with chronic pain: a prospective cohort study

BackgroundOpioid misuse can complicate chronic pain management, and the non-medical use of opioids is a growing public health problem. The incidence and risk factors for opioid misuse in patients with chronic pain, however, have not been well characterized. We conducted a prospective cohort study to determine the one-year incidence and predictors of opioid misuse among patients enrolled in a chronic pain disease management program within an academic internal medicine practice.MethodsOne-hundred and ninety-six opioid-treated patients with chronic, non-cancer pain of at least three months duration were monitored for opioid misuse at pre-defined intervals. Opioid misuse was defined as: 1. Negative urine toxicological screen (UTS) for prescribed opioids; 2. UTS positive for opioids or controlled substances not prescribed by our practice; 3. Evidence of procurement of opioids from multiple providers; 4. Diversion of opioids; 5. Prescription forgery; or 6. Stimulants (cocaine or amphetamines) on UTS.ResultsThe mean patient age was 52 years, 55% were male, and 75% were white. Sixty-two of 196 (32%) patients committed opioid misuse. Detection of cocaine or amphetamines on UTS was the most common form of misuse (40.3% of misusers). In bivariate analysis, misusers were more likely than non-misusers to be younger (48 years vs 54 years, p < 0.001), male (59.6% vs. 38%; p = 0.023), have past alcohol abuse (44% vs 23%; p = 0.004), past cocaine abuse (68% vs 21%; p < 0.001), or have a previous drug or DUI conviction (40% vs 11%; p < 0.001%). In multivariate analyses, age, past cocaine abuse (OR, 4.3), drug or DUI conviction (OR, 2.6), and a past alcohol abuse (OR, 2.6) persisted as predictors of misuse. Race, income, education, depression score, disability score, pain score, and literacy were not associated with misuse. No relationship between pain scores and misuse emerged.ConclusionOpioid misuse occurred frequently in chronic pain patients in a pain management program within an academic primary care practice. Patients with a history of alcohol or cocaine abuse and alcohol or drug related convictions should be carefully evaluated and followed for signs of misuse if opioids are prescribed. Structured monitoring for opioid misuse can potentially ensure the appropriate use of opioids in chronic pain management and mitigate adverse public health effects of diversion.

The critical role of nursing in successful opioid withdrawal in chronic non-cancer pain

Maintenance opioid use in chronic non-cancer pain treatment is widespread and controversial. A recent article in Mayo Clinic Proceedings examined this issue and concluded that, “patients who have symptomatically severe and functionally disabling pain, while receiving maintenance opioid therapy, can obtain significant benefit from rehabilitative treatment that incorporates opioid withdrawal.” 1Rome, J.D. et al., Mayo Clinic Proceedings, 2004). The purpose of the present study is to describe the process of opioid withdrawal undertaken in a multidisciplinary pain rehabilitation program with the emphasis on the specific roles nurses play in the success of this intervention. A multidisciplinary approach is utilized, with two levels of nursing care, aimed at improving patient’s emotional and physical functioning and quality of life. A key component in this pain rehabilitation effort is a conservative philosophy of analgesic use for chronic non-cancer pain. Opioid medications are discontinued, while self-management strategies are implemented including exercise, relaxation skills, moderation and healthy lifestyle changes. The masters prepared Clinical Nurse Specialist (CNS) and baccalaureate prepared RN, supervised by the MD, assist patients with medication changes using a systematic, gradual method of reducing and discontinuing opioids for chronic pain management. The CNS structures opioid tapers utilizing prescriptive privileges, advanced assessment, and education/interventions focusing on chemical health and wellness. The RN monitors daily opioid tapers including monitoring patient self-administration of medications, assessing withdrawal symptoms, and reinforcing alternative coping techniques for pain management. Measures of pain severity, interference due to pain, activity level, perceived life control, affective distress, depression and catastrophizing have been used to compare opioid and nonopioid groups within this pain rehabilitation center. This paper will illustrate specific interventions utilized by pain rehabilitation nurses that directly contribute to successful opioid withdrawal and improvement in emotional and physical functioning for patients with chronic pain. 1Rome, J.D. et al., Mayo Clinic Proceedings, 2004). Maintenance opioid use in chronic non-cancer pain treatment is widespread and controversial. A recent article in Mayo Clinic Proceedings examined this issue and concluded that, “patients who have symptomatically severe and functionally disabling pain, while receiving maintenance opioid therapy, can obtain significant benefit from rehabilitative treatment that incorporates opioid withdrawal.” 1Rome, J.D. et al., Mayo Clinic Proceedings, 2004). The purpose of the present study is to describe the process of opioid withdrawal undertaken in a multidisciplinary pain rehabilitation program with the emphasis on the specific roles nurses play in the success of this intervention. A multidisciplinary approach is utilized, with two levels of nursing care, aimed at improving patient’s emotional and physical functioning and quality of life. A key component in this pain rehabilitation effort is a conservative philosophy of analgesic use for chronic non-cancer pain. Opioid medications are discontinued, while self-management strategies are implemented including exercise, relaxation skills, moderation and healthy lifestyle changes. The masters prepared Clinical Nurse Specialist (CNS) and baccalaureate prepared RN, supervised by the MD, assist patients with medication changes using a systematic, gradual method of reducing and discontinuing opioids for chronic pain management. The CNS structures opioid tapers utilizing prescriptive privileges, advanced assessment, and education/interventions focusing on chemical health and wellness. The RN monitors daily opioid tapers including monitoring patient self-administration of medications, assessing withdrawal symptoms, and reinforcing alternative coping techniques for pain management. Measures of pain severity, interference due to pain, activity level, perceived life control, affective distress, depression and catastrophizing have been used to compare opioid and nonopioid groups within this pain rehabilitation center. This paper will illustrate specific interventions utilized by pain rehabilitation nurses that directly contribute to successful opioid withdrawal and improvement in emotional and physical functioning for patients with chronic pain. 1Rome, J.D. et al., Mayo Clinic Proceedings, 2004).

The Trilateral Opioid Contract: Bridging the Pain Clinic and the Primary Care Physician Through the Opioid Contract

We have extended the traditional use of opioid contracts to involve the primary care physician (PCP). The PCP was asked to collaborate with the pain specialist's decision to use opioids by cosigning an opioid contract. Explicit in the agreement was the understanding that the primary care physician would assume prescribing the refills for these medications once the opioid regimen had become stabilized. The present study was a retrospective chart review of the first 81 patients with non-malignant chronic pain who received an opioid agreement requiring the participation of the primary care physician. Sixty-nine of the 81 patients (85%) agreed to the terms of the contract initially, but only 50 of these 69 individuals (72%) successfully obtained their PCP's written agreement for the prescribing of opioids for chronic pain management. Despite expecting reluctance on the part of the PCP to enter into this agreement, the low compliance rate was due to lack of commitment on the part of the patient, who either refused to sign the contract outright or, after initially agreeing to sign the contract, did not have it signed by the PCP. If the PCP did not agree to sign the opioid contract, the patient was tapered off the medication. If the contract was approved and signed by the PCP, there were no subsequent reversals by this physician in terms of agreeing to continue to prescribe opioids. In all cases in which a contract was completed, the patient was successfully stabilized on an appropriate opioid regimen and then discharged back to the care of the PCP for long-term opioid treatment. The opioid contract may be an effective tool for networking specialty and primary care services in the delivery of chronic opioid therapy.

Opioids in chronic pain management: is there a significant risk of addiction?

In the last decade there has been significant controversy about the appropriateness, efficacy, safety, and wisdom of treating chronic pain patients (CPPs) with opioids. Arguments against their use have included concerns about tolerance, dependence, addiction, persistent side effects, and interference with physical or psychosocial functioning. However, considerable experience and research with long-term cancer pain treatment suggests that in appropriately selected patients, opioids have a low morbidity, and a low addiction potential, and in addition to the primary analgesic action, can facilitate reduction in suffering, enhance functional activity level, and improve quality of life without significant risk of addictive behaviors. Some patients, however, are at risk. Risk factors for addiction are discussed in this article.