Evidence-based pain medicine for primary care physicians.

The last several decades have seen a marked increase in both the recognition and treatment of chronic pain. Unfortunately, patients frequently misunderstand both the nature of pain and the best practices for its treatment. Because primary care physicians treat the majority of chronic pain, they are ideally situated to provide evidence-based pain care. The majority of the medical evidence supports a biopsychosocial model of pain that integrates physical, emotional, social, and cultural variables. The goal of this primer is to assist primary care physicians in their understanding of pain, evaluation of the chronic pain patient, and ability to direct evidence-based care. This article will discuss the role of physical rehabilitation, pain psychology, pharmacotherapy, and procedural interventions in the treatment of chronic pain. Given the current epidemic of drug-related deaths, particular emphasis is placed on the alternatives to opioid therapy. Unfortunately, death is not the only significant complication from opioid therapy, and this article discusses many of the most common side effects. This article provides general guidelines on the most appropriate utilization of opioids with emphasis on the recent Centers for Disease Control and Prevention guidelines, risk stratification, and patient monitoring. Finally, the article concludes with the critical role that a pain medicine specialist can play in the management of patients with chronic pain.

Compliance with Opioid Therapy: Distinguishing Clinical Characteristics and Demographics Among Patients with Cancer Pain.

Background: Because an increase of patients who misuse opioids has been identified in our cancer clinical setting through urine drug testing (UDT) and the Screener and Opioid Assessment for Patient's with Pain-Short Form (SOAPP-SF), we conducted this retrospective cohort study to identify patient characteristics that are associated with UDT that indicates noncompliance. Methods: Over a two-year period, 167 of 8,727 patients (2.4%) seen in the pain clinic and who underwent UDT were evaluated to determine compliance with prescribed opioid regimens. Descriptive clinical and demographic data were collected, and group differences based on compliance with opioid therapy were evaluated. Results: Fifty-eight percent of the patients were noncompliant with their prescribed opioid therapy. Noncompliant patients were younger than compliant patients, with a median age of 46 vs 49 years (P = 0.0408). Noncompliant patients were more likely to have higher morphine equivalent daily doses; however, the difference was not statistically significant. Patients with a history of alcohol (ETOH) (P = 0.0332), illicit drug use (P = 0.1014), and smoking (P = 0.4184) were more likely noncompliant. Univariate regression analysis showed that a history of ETOH use (P = 0.034), a history of anxiety (P = 0.027), younger age (P = 0.07), and a SOAPP-SF score of 4 or higher (P = 0.05) were associated with an abnormal UDT. Conclusions: History of ETOH use, anxiety, high SOAPP-SF score, and younger age were associated with UDT that indicates noncompliance. Given the very small percentage of UDT testing, it is quite likely that a significant number of patients who did not undergo UDT were also nonadherent with treatment recommendations.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Modulate the Function of Myelinated Fibers after Chemotherapy: A Quantitative Sensory Testing Study.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) have sufficient scientific support for their use as tissue protectors. Preliminary studies suggest that their angiotensin-II type 2 receptor (AT2R)-blocking properties have a beneficial profile in the treatment of neuropathic pain. OBJECTIVES: The purpose of the current study was to quantify the extent of the somatosensory effects of ACEI and ARB in cancer patients with chemotherapy-induced peripheral neuropathy. STUDY DESIGN: We performed a retrospective review of cancer patients with peripheral neuropathy of the upper limbs induced by known neurotoxic anti-cancer agents. SETTING: Pain Medicine department at academic tertiary care cancer center. METHODS: Using our quantitative sensory testing (QST) data bank, we retrospectively compared the tactile function and the touch, sharp, and thermal thresholds of patients who were previously receiving ACEI or ARB for high blood pressure with these variables in controls who were not receiving ACEI or ARB. RESULTS: Of the 209 patients available for analysis, 145 met inclusion criteria. Baseline characteristics of patients included were generally similar. We identified 29 patients who were receiving AT2R inhibitors prior to starting chemotherapy. Touch thresholds were statistically lower in the thenar aspect of hand in the study group (patients who received AT2R inhibitors) than in the control group [mean (± SD), median 3.03 g (± 11.05), median 0.56 g and 6.75 g (± 18.28), 0.56 g, respectively (P = 0.0441)]. Similarly, the cold pain threshold was statistically higher at the thenar area for the study group [mean (± SD), median 13.23°C (± 8.02), 11.73°C] than for controls [9.89°C (± 6.62), 10.05°C (P = 0.0369)]. LIMITATIONS: Inadequacies in the original data acquisition and documentation of the QST and the medical records could not be addressed due to the retrospective nature of the study. Similarly, a discrepancy on the size of the comparison groups could not be reconciled. In addition, based on the available information and the lack of documented concomitant pain levels, we did not find an objective parameter able to correlate the QST findings with pain levels. CONCLUSIONS: AT2R inhibitors might offer partial and selective neuroprotective qualities of the myelinated fibers A-beta; and A-delta in cancer patients who receive neurotoxic chemotherapy.

Reporting of Design Features and Analysis Details in Randomized Clinical Trials of Procedural Treatments for Cancer Pain: An ACTTION Systematic Review.

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the reporting of randomized clinical trials investigating procedural treatments (eg, nerve blocks, targeted drug delivery) for cancer pain, with a focus on aspects that are particularly challenging in these trials. METHODS: This article presents results from a systematic review of reporting of randomized clinical trials of procedural interventions for cancer pain. Articles were identified by searching PubMed from 1966 to June 2014. Data related to quality of reporting are presented for early (1985-2004) and late periods (2005-2014). RESULTS: A total of 35 published trials were included. Approximately two-thirds of the articles clearly indicated the level of blinding. Only 26% reported a primary outcome measure. Less than half explicitly reported the number of patients who completed the trial, and only 1 reported a method that was used to accommodate missing data. Almost one-third of articles included a responder analysis, all of which specified the definition of a responder. CONCLUSIONS: The goal of highlighting these deficiencies in reporting is to promote transparent reporting of details affecting the completion and interpretation of procedural cancer pain trials so that their quality can be more easily evaluated.

Effectiveness of Splanchnic Nerve Neurolysis for Targeting Location of Cancer Pain: Using the Pain Drawing as an Outcome Variable.

The effectiveness of splanchnic nerve neurolysis (SNN) for cancer-related abdominal pain has been investigated using numeric pain intensity rating as an outcome variable. The outcome variable in this study used the grid method for obtaining a targeted pain drawing score on 60 patients with pain from pancreatic or gastro-intestinal primary cancers or metastatic disease to the abdominal region. Results demonstrate excellent inter-rater agreement (intra-class correlation [ICC] coefficient at pre-SNN = 0.97 and ICC at within one month post-SNN = 0.98) for the grid method of scoring the pain drawing and demonstrate psychometric generalizability among patients with cancer-related pain. Using the Wilcoxon signed rank test and associated effect sizes, results show significant improvement in dispersion of pain following SNN. Effect sizes for the difference in pre-SNN to 2 post-SNN time points were higher for the pain drawing than for pain intensity rating. Specifically, the effect size difference from pre- to within one month post-SNN was r = 0.42 for pain drawing versus r = 0.23 for pain intensity rating. Based on a smaller subset of patients who were seen within 1 - 6 months following SNN, the effect size difference from pre-SNN was r = 0.46 for pain drawing versus r = 0.00 for pain intensity rating. Collectively, these data support the use of the pain drawing as a reliable outcome measure among patients with cancer pain for procedures such as SNN that target specific location and dispersion of pain.

The Effectiveness of Alcohol Versus Phenol Based Splanchnic Nerve Neurolysis for the Treatment of Intra-Abdominal Cancer Pain.

UNLABELLED: Pancreatic and other upper abdominal organ malignancies can produce intense visceral pain syndromes that are frequently treated with splanchnic nerve neurolysis (SNN) or celiac plexus neurolysis (CPN). Although commonly performed with either alcohol or phenol, there is scant literature on the comparative effectiveness, duration of benefit, and complication profile comparing the 2 agents. This study presents a retrospective chart review of 93 patients who underwent SNN for cancer-related abdominal pain in order to describe patient characteristics, examine comparative efficacy, duration of benefit, and incidence of complications with alcohol vs. those of phenol. Consistent with previous studies, SNN reduced reported pain scores while not significantly reducing opioid consumption. No difference in pain outcomes was found comparing alcohol versus phenol based neurolytic techniques. Celiac axis tumor infiltration and pre-procedural local radiation therapy did not change the effectiveness of the procedure. Our data demonstrated that 44.57% of patients had = 30% pain reduction while 43.54% did not have pain reduction. Interestingly, the procedure produced significant improvements in anxiety, depression, difficulty thinking clearly, and feeling of well-being. In addition, no difference in complications was seen between the agents either. SNN was an effective and relatively safe procedure for the treatment of pain associated with pancreatic and other upper abdominal organ malignancies in our sample of patients. Choice of neurolytic agent can appropriately be left to the clinical judgment and local availability of the treating physician. The change in ancillary symptoms has a theoretical basis that supports a biopsychosocial model of pain since changes in one target area (pain) impact other related ones (depression and anxiety). KEY WORDS: Celiac plexus, splanchnic nerves, neurolysis, nerve block, alcohol, ethanol, phenol, pain, cancer pain, abdominal pain, visceral pain, symptom assessment.

Lumbar subarachnoid hematoma following an epidural blood patch for meningeal puncture headache related to the implantation of an intrathecal drug delivery system.

Persistent meningeal puncture headache (MPH) is a known complication following both intentional and unintentional puncture of the dura mater.  We present a case of persistent MPH following implantation of an intrathecal drug delivery system (IDDS). Two separate epidural blood patches (EBP) were performed under radiographic guidance with contrast visualization of the epidural space on postoperative days 16 and 28, respectively. The case was complicated by the development of a symptomatic lumbar subarachnoid hematoma diagnosed on postoperative day 35. The patient subsequently underwent a laminectomy, evacuation of the hematoma, and explanation of the IDDS. This case illustrates a potential unique morbidity associated with the EBP in a patient with an IDDS. The report concludes with a brief review of MPH followed by a discussion of possible mechanisms underlying this complication.

Infectious complications related to intrathecal drug delivery system and spinal cord stimulator system implantations at a comprehensive cancer pain center.

BACKGROUND: Intrathecal drug delivery (IDD) and spinal cord stimulator (SCS) systems are implantable devices for the management of both chronic and cancer pain. Although these therapies have favorable long-term outcomes, they are associated with occasional complications including infection. The incidence of infectious complications varies from 2 - 8% and frequently requires prolonged antibiotics and device revision or removal. Cancer patients are particularly susceptible to infectious complications because they are immunocompromised, malnourished, and receiving cytotoxic cancer-related therapies. OBJECTIVE: Determine if cancer pain patients have a higher incidence of infectious complications following implantation of IDD or SCS systems than non-cancer pain patients. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary comprehensive cancer hospital. METHODS: Following local Institutional Review Board (IRB) approval, we collected data on infectious complications for IDD and SCS systems implanted at MD Anderson Cancer Center for the treatment of cancer and chronic pain. The examined implants were performed from July 15, 2006, to July 14, 2009. In addition, we obtained data regarding patient comorbidities and perioperative risk factors to assess their impact on infectious complications. RESULTS: One hundred forty-two devices were implanted in 131 patients during the examined period. Eighty-three of the devices were IDD systems and 59 were SCS systems. Eighty percent of the patients had a diagnosis of cancer. Four infectious complications were noted with an overall infectious risk of 2.8%. The infection rate was 2.4% for IDD systems versus 3.4% for SCS systems (P = 1). All infections were at the implantable pulse generator (IPG) or pump pocket site. The rate of infection was 2.7% for cancer patients and 3.3% for non-cancer patients (P = 1). Neither the perioperative administration of prophylactic antibiotics (P = 0.4) nor the National Nosocomial Infection Surveillance (NNIS) risk level for individual patients (P = 0.15) were statistically associated with infectious complication. The mean surgical time was longer for cases with infection at 215 ± 93 minutes versus 132 ± 52 minutes for those without infection which was statistically significant (P = 0.02). LIMITATIONS: The major limitation of this study is that it was a retrospective analysis. An additional limitation is that 51(38.9%) of our patients either died or were lost to follow-up during the year following implantation which may have led to an underestimation of our infection rates. CONCLUSIONS: The experience of this tertiary cancer pain center demonstrates that infectious complications following implantation of IDD and SCS systems are relatively rare events in cancer patients. Contrary to our initial hypothesis, no difference was found in the infection rate between cancer and non-cancer patients. The main factor associated with increased risk of infectious complications was increased surgical time, indicating a need to minimize patient time in the operating room. The low infectious complication rate seen in this series compared to previous reports in non-cancer patients is likely multifactorial in nature.

Intrathecal oxytocin inhibits visceromotor reflex and spinal neuronal responses to noxious distention of the rat urinary bladder.

BACKGROUND AND OBJECTIVES: Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation. METHODS: Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 seconds; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings. RESULTS: Oxytocin doses of 0.15 or 1.5 µg inhibited VMRs to UBD by 37% ± 8% and 68% ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY-receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76% ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes. CONCLUSIONS: These results argue that intrathecal OXY produces an OXY receptor-specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.

Spinal nerve ligation decreases γ-aminobutyric acidB receptors on specific populations of immunohistochemically identified neurons in L5 dorsal root ganglion of the rat.

This study examined the distribution of γ-aminobutyric acid (GABA)(B) receptors on immunohistochemically identified neurons, and levels of GABA(B(1)) and GABA(B(2)) mRNA, in the L4 and L5 dorsal root ganglia (DRG) of the rat in the absence of injury and 2 weeks after L5 spinal nerve ligation. In uninjured DRG, GABA(B(1)) immunoreactivity colocalized exclusively with the neuronal marker (NeuN) and did not colocalize with the satellite cell marker S-100. The GABA(B(1)) subunit colocalized to >97% of DRG neurons immunoreactive (IR) for neurofilament 200 (N52) or calcitonin gene-related peptide (CGRP), or labeled by isolectin B4 (IB4). Immunoreactivity for GABA(B(2)) was not detectable. L5 spinal nerve ligation did not alter the number of GABA(B(1)) -IR neurons or its colocalization pattern in the L4 DRG. However, ligation reduced the number of GABA(B(1)) -IR neurons in the L5 DRG by ≈38% compared with sham-operated and naïve rats. Specifically, ligation decreased the number of CGRP-IR neurons in the L5 DRG by 75%, but did not decrease the percent colocalization of GABA(B(1)) in those that remained. In the few IB4-positive neurons that remained in the L5 DRG, colocalization of GABA(B(1)) -IR decreased to 75%. Ligation also decreased levels of GABA(B(1)) and GABA(B(2)) mRNA in the L5, but not the L4 DRG compared with sham-operated or naïve rats. These findings indicate that the GABA(B) receptor is positioned to presynaptically modulate afferent transmission by myelinated, unmyelinated, and peptidergic afferents in the dorsal horn. Loss of GABA(B) receptors on primary afferent neurons may contribute to the development of mechanical allodynia after L5 spinal nerve ligation.