Management Of Chronic Pain States Research Articles

Methadone

Methadone

Use of ultrasound-guided cryotherapy for the management of chronic pain states

Study ObjectiveTo report the use of ultrasound for cyroablation of purely sensory nerves for long-term relief of pain because the use of ultrasound enhances accuracy while minimizing injury to surrounding structures. DesignCase series of three patients with positive long-term outcomes. SettingOutpatient Pain Management Clinic associated with a large, university affiliated, tertiary-care community hospital. Patients3 ASA physical status 2 and 3 patients who were treated for intercostal neuralgia secondary to surgical incision or vertebral fractures. InterventionsThese patients had failed various medical therapies but had positive responses to diagnostic intercostal nerve blocks. They underwent lesioning of the culprit nerves (with the use of ultrasound). Measurements and Main ResultsPain scores were recorded using a numeric rating scale (NRS), and were solicited preprocedurally and postprocedurally, and once again after longterm follow-up (> 2 mos). Longterm (> 2 mos) relief of symptoms from established, chronic pain conditions was achieved with cryotherapy with ultrasound guidance. ConclusionsNeuro-ablative procedures using cryotherapy have been well reported. The use of ultrasound with cryotherapy facilitates direct visualization of the anatomy and aids in avoidance of vital vascular and pleural structures.

Dissociable cortical and ventral striatal responses to painful somatosensory stimulation measured using functional MRI imaging

INTRODUCTION Investigation of the neural responses of chronic pain have traditionally involved establishing the BOLD fMRI response to acute pain in a nodal network that has been referred to as the ‘pain matrix’ or the ‘pain neuromatrix’ (1). However, Melzack originally used the term ‘matrix’ because the system to which he referred was multimodal in function and lacked specificity. This might explain why, over 20 years after the term was coined, there has been little translational benefit to patients in terms of improved management of chronic pain states despite numerous studies examining the ‘pain matrix response’. The basal ganglia form part of this matrix and are worthy of further investigation. Destruction of nigrostriatal neurones in the ventral basal ganglia are associated with reduced pain thresholds, the inverse effect occurring with nigrostriatal stimulation(2). However, inactivation of the accumbens core in the ventral basal ganglia with local anaesthetic has demonstrated a hyperalgesic response (3). Molecular imaging has been used to examine the differential roles of dorsal and ventral basal ganglia in pain perception (4) . These authors found that whilst nigrostriatal D2-dopamine activity correlates with sensory and affective ratings, in accumbens the dopamine response is positively associated with negative affect and fear ratings during pain, aspects of the pain experience that are thought to better explain interindividual variations in chronic pain (5) and response to analgesia. In establishing a region of interest approach to the investigation of chronic pain through the application of acutely painful stimuli, the ventral striatum may therefore be an important target. The role of the ventral striatum in response to aversive stimuli is receiving increasing attention, in counterpart to studies of its responsivity to rewarding stimuli. Recent work (6) suggests that the differential striatal responses to acute pain may provide a meaningful insight into the neural substrates of chronic pain perception, including idiopathic pain disorders and the functional somatic syndromes, where activation of the ‘pain matrix’ as a whole has proved unable to. We have investigated the brain response to somatosensory pain, specifically examining the response of the ventral striatum in contrast to other components of the ‘pain matrix’.

Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases

BackgroundMany studies have shown the antinociceptive effects of cannabinoid (CB) agonists in different models of pain. Herein, we have investigated their relevance in neuropathic pain induced by brachial plexus avulsion (BPA) in mice.Methodology/Principal FindingsMice underwent BPA or sham surgery. The mRNA levels and protein expression of CB1 and CB2 receptors were assessed by RT-PCR and immunohistochemistry, respectively. The activation of glial cells, MAP kinases and transcription factors were evaluated by immunohistochemistry. The antinociceptive properties induced by cannabinoid agonists were assessed on the 5th and 30th days after surgery. We observed a marked increase in CB1 and CB2 receptor mRNA and protein expression in the spinal cord and dorsal root ganglion, either at the 5th or 30th day after surgery. BPA also induced a marked activation of p38 and JNK MAP kinases (on the 30th day), glial cells, such as microglia and astrocytes, and the transcription factors CREB and NF-κB (at the 5th and 30th days) in the spinal cord. Systemic treatment with cannabinoid agonists reduced mechanical allodynia on both the 5th and 30th days after surgery, but the greatest results were observed by using central routes of administration, especially at the 30th day. Treatment with WIN 55,212-2 prevented the activation of both glial cells and MAP kinases, associated with an enhancement of CREB and NF-κB activation.Conclusions/SignificanceOur results indicate a relevant role for cannabinoid agonists in BPA, reinforcing their potential therapeutic relevance for the management of chronic pain states.

Roles of microglia and purinoceptors in pain

There is a abundant evidence that both extracellular and intracellular ATP have an important role in pain signaling.The focus of attention is now on the possible roles and mechanism of ATP and its receptors in chronic pain states, particularly in neuropathic pain. After the body is stimulated, the activated microglia can over express P2X4R and other ATP receptors, resulting in the release of BDNF ,IL-1β ,TNF-α、IL-6、NO.Understanding the key roles of these ATP receptors may provide new strategies for management of chronic pain states. Key words: Microglia; ATPreeeptors; P2X4; Pain

Cardiotoxicity of Oral Methadone as an Analgesic–-Recommendations for Safe Use

Once used only as third-line therapy in the management of chronic pain states, methadone is now being used as first- and second-line therapy. Most risks and the stigma associated with methadone use have been known for years. Only over the past decade or so have the unique pharmacokinetic-pharmacodynamic properties and methods for conversion from other opioids to methadone been established. Pertinent English-language literature was obtained from MEDLINE/PUBMED and EMBASE searches (1966-June 2009). This paper provides an overview of the cardiotoxicity of oral methadone, with an emphasis on its use as an analgesic. Cardiotoxicity during its use in the maintenance of opioid addiction has also been reviewed due to the wealth of epidemiologic, risk factor, and correlative analytic data contained therein. A series of recommendations are provided to improve the cardiac safety profile of oral methadone used for analgesia. In addition, there is a discussion of settings and patient types which may impact upon these recommendations.

Peroxynitrite Decomposition Catalysts as Adjuncts to Morphine for the Management of Chronic Pain States

Severe pain reduces life quality in patients with inflammatory and neoplastic diseases (i.e lung cancer), partly because reduced analgesic effectiveness of chronic opiate therapy leads to escalating doses and distressing side effects. The mechanisms involved are poorly understood. Peroxynitrite (ONOO−), a potent pro‐inflammatory and pro‐apoptotic reactive species, is now implicated in hyperalgesia of several etiologies. In mice we showed that repeated morphine administration leads to nitrotyrosine (NT) formation in the dorsal horn of the spinal cord, with NT as a reliable marker for ONOO−. The role of ONOO− was proven by showing that co‐administering morphine with novel and potent ONOO− decomposition catalysts such as Mn(III) ortho alkylpyridylporphyrins, attenuated NT formation and prevented antinociceptive tolerance at doses devoid of behavioural side effects and up to 300 fold‐lower than previously used Fe or Mn porphyrins. These effects coincided with: 1) nitration of MnSOD, a glutamate transporter, and glutamine synthase; 2) increased formation of pro‐inflammatory cytokines; and 3) oxidative DNA damage and activation of the nuclear factor poly(ADP‐ribose) polymerase. These findings support our central hypothesis that ONOO− is critical to the development of morphine‐induced antinociceptive tolerance providing the rationale towards the development of ONOO− decomposition catalysts as adjuncts to opiates for the management of chronic pain.

Brain Response to Visceral Aversive Conditioning: A Functional Magnetic Resonance Imaging Study

Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.

Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure

The opioid analgesics, commonly exemplified by morphine, represent the best option for the treatment of severe pain and for the management of chronic pain states, of both malignant and nonmalignant origin. It is well recognized that the prolonged use of opioids is associated with a requirement for ever-increasing doses in order to maintain pain relief at an acceptable and consistent level. This phenomenon is termed analgesic tolerance. While the concept that tolerance can develop as a result of cellular adaptations to the presence of the opioid has been proposed, it is now becoming abundantly clear that tolerance may also be related to a state of hyperalgesia that results from exposure to the opioid itself. Patients who receive long-term opioid therapy sometimes develop unexpected, abnormal pain. Similar paradoxical opioid-induced pain has been confirmed in a number of animal studies, even during the period of continuous opioid delivery. A number of recent studies have demonstrated that such pain may be secondary to neuroplastic changes that occur in the brain and spinal cord. One such change may be the activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM) elicited in part by increased activity of cholecystokinin (CCK) in the RVM. A cascade of pronociceptive events may follow, such as opioid-induced upregulation of spinal dynorphin levels that promotes enhanced input from primary afferent nociceptors. This mechanism appears to depend on intact descending pathways from the RVM, since interrupting this pathway abolishes enhanced abnormal pain. Furthermore, extended opioid exposure also can elicit increased calcitonin gene related peptide (CGRP) and substance P expression in the dorsal root ganglia. It is probable that increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance because the same manipulations that block abnormal pain also block antinociceptive tolerance. Taken together, such studies show that opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin, and enhanced, evoked release of excitatory transmitters from primary afferents. These adaptive changes in response to sustained exposure to opioids indicate the need for the evaluation of the clinical consequences of long-term opioid administration. Additionally, these findings suggest a need for novel chemistry involving design of agents that may counteract opiate-induced neuroplastic adaptations resulting in pain relief without analgesic tolerance.

Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid–induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients.

Structure quality of independent physicians for pain management--is there a standard?

Evidence based standards for structure quality in out-patient management of chronic pain states do not exist. Therefore we tried to evaluate if german standards for outpatient management of chronic pain states which are based on opinions of experts for pain management influence the outcome quality of independent physicians for treatment of chronic low back pain. 35 independent physicians, selected on a voluntary basis from 2100 physicians of a bavarian greater district with 1,6 Mio. inhabitants, and one outpatient treatment facility for pain patients of the university of Erlangen-Nuremberg have been evaluated by questionnaires. Questions examined certain structural conditions of the treatment facility as compared to german guidelines for outpatient treatment of pain patients ("Schmerztherapievereinbarung"). 157 patients suffering from chronic low back pain documented before and after a treatment interval of 6 months their pain intensity during the last 24 hours (numeric rating scale), the interference of pain with daily living (german version of the Brief Pain Inventory) and their quality of life (SF-36). Pre-post changes have been used as parameters for outcome quality. Neither baseline data nor pre-post differences of outcome parameter did correlate significantly with the scores of structure quality (17-71% of maximum) of the treatment facilities. However, multimodal therapy programs have not been used for pain management. Structural indicators of german guidelines for outpatient treatment of pain patients ("Schmerztherapievereinbarung") are not sufficient to improve outcome quality of patients with chronic back pain. Multimodal therapy programs have been shown to be effective in chronic back pain and should be implemented in the guidelines.

Fibromyalgia and Pain Management: In reply

Fibromyalgia and Pain Management: In reply

Complete prevention but stimulus-dependent reversion of morphine tolerance by the glycine/NMDA receptor antagonist (+)-HA966 in neuropathic rats.

Tolerance to the analgesic effect of morphine complicates the management of chronic pain states. The authors studied the ability of the glycine/N-methyl-D-aspartate receptor antagonist (+)-HA966 to modify morphine tolerance in a rat model of neuropathic pain. Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. The 4-day pretreatment regimens with two daily subcutaneous injections of saline and saline, saline and morphine (10 mg/kg), (+)-HA966 (2.5 mg/kg) and morphine, or (+)-HA966 and saline were begun on post-operative day 12 to test the ability of (+)-HA966 to prevent the development of tolerance. Behavioral experiments were performed on postoperative day 16, when the pain-related behavior reached a stable maximum. The effect of an acute dose of morphine (1 mg/kg intravenously) was tested against both mechanical (vocalization threshold to paw pressure) and thermal (struggle latency to hind paw immersion into a 46 degrees C hot-water bath) stimuli. In addition, to test the ability of a single injection of (+)-HA966 to reverse established morphine tolerance, groups of morphine-pretreated rats received injections of either (+)-HA966 (2.5 mg/kg subcutaneously) and morphine (1 mg/kg intravenously), saline and morphine, or (+)-HA966 and saline. Baseline vocalization thresholds and struggle latencies did not differ in the various pretreatment groups, indicating that the pretreatments had no effect on pain-related behavior. Coadministration of (+)-HA966 prevented the reduction of the effect observed with morphine alone in both the mechanical test and the thermal test. (+)-HA966 reversed morphine tolerance in the thermal but not in the mechanical test. (+)-HA966 prevented morphine tolerance in both mechanical and thermal tests but reversed established morphine tolerance in the thermal test only.

Neuroanatomical Review of Visceral Pain

Visceral afferent information is processed centrally by the nervous system. The central connections of these afferents are widespread. Although the encoding of visceral pain is still creating much debate, evidence exists for mechanisms of central sensitization and mechanisms of referred pain to somatic structures, leading to possible trophic changes in these structures.The autonomic nervous system innervates the viscera. As with the somatic nervous system, it too is vulnerable in certain areas to compromise, within the thoracic, abdominal and pelvic cavities for example. If the sympathetic nervous system is sensitized then alterations in sympathetic outflow could lead to trophic alteration in target tissue, as well as the maintenance of pain states.If, at a physical level, manual therapists are to evaluate these central and sympathetic changes that may take place due to sensitized visceral and sympathetic input in the generation and maintenance of pain, then a physical assessment of the visceral and supporting fascial network must be made in the management of chronic pain states.

Complications of antidepressants, anticonvulsants, and antiarrhythmics for chronic pain management

Adjunctive drugs play an important role in the management of chronic pain states. Recent analysis of previous studies has confirmed the efficacy of both anticonvulsant and antidepressant medications in the treatment of a variety of chronic pain conditions. There are few trials investigating the use of antiarrhythmic drugs in chronic pain. The studies that exist do suggest that antiarrhythmics may be of use in some cases. There are serious toxicities associated with all of these agents. Many of these are so troublesome as to require cessation of the drug. There are also some alarming idiosyncratic reactions associated with their use. Recent advances have included the introduction of gabapentin and lamotrigine. Both of these have significantly fewer side effects and are better tolerated. Currently there is little clinical data regarding their efficacy in chronic pain states. Newer antidepressants do not appear to be significantly better than placebo in treating pain. Their faster onset and fewer side effects may make them better tolerated in the treatment of associated depression. Antiarrhythmic agents, due to potentially lethal side effects, are best reserved for resistant pain unresponsive to more conventional drugs.

Intravenous Infusion of Lidocaine in the Management of Chronic Pain States

Intravenous Infusion of Lidocaine in the Management of Chronic Pain States

Ketorolac

Ketorolac is a non-steroidal agent with potent analgesic and moderate anti-inflammatory activity. It is administered as the tromethamine salt orally, intramuscularly, intravenously, and as a topical ophthalmic solution. Clinical studies indicate single-dose efficacy greater than that of morphine, pethidine (meperidine) and pentazocine in moderate to severe postoperative pain, with some evidence of a more favourable adverse effect profile than morphine or pethidine. In single-dose studies ketorolac has also compared favourably with aspirin, paracetamol (acetaminophen) and a few other non-steroidal anti-inflammatory drugs. If further investigation confirms the initially favourable findings regarding efficacy and tolerability, ketorolac will be a useful alternative to opioid agents in postsurgical pain. It may well also find use in acute musculoskeletal pain, where it appears at least as effective as other agents with which it has been compared. From the limited clinical data available, ketorolac also seems promising in the treatment of ocular inflammatory conditions. Additional multiple-dose studies are required to evaluate fully the potential of ketorolac in the management of chronic pain states where it has shown superior efficacy to aspirin. In summary, ketorolac offers promise as an alternative to opioid and to other nonsteroidal analgesics in ameliorating moderate to severe postsurgical pain, and with wider clinical experience may find a place in the treatment of acute musculoskeletal and other pain states, and ocular inflammatory conditions.

Motivational effects of opioids in an animal model of prolonged inflammatory pain: alteration in the effects of κ-but not of μ-receptor agonists

An unbiased preference conditioning procedure was used to characterize and compare the motivational effects of opioids in naive rats and those suffering from the prolonged pain associated with Freund's adjuvant (FA)-induced inflammation of one hind limb. The μ-opioid agonist morphine functioned as a reinforcer in naive animals, producing marked preferences for the drug-paired place. Similarly, rats injected with FA 7 days prior to conditioning exhibited a preference for the morphine place and the magnitude of this effect did not differ between groups. Administration of the κ-opioid receptor agonist U-69593 to naive rats produced dose-related place aversions. The aversive effect of this κ-agonist was, however, abolished in FA-treated rats. Thus, regardless of the dose administered, U-69593 produced conditioning similar to that observed in response to saline. These data suggest that κ-agonists may lack aversive effects in subjects experiencing prolonged noxious stimulation and as such may be effective therapeutic agents in the management of chronic pain states.

Psychotherapy for Chronic Pain

SUMMARY Although research evidence is still lacking for a definitive appraisal, the relative efficacy of psychotherapy in the management of chronic pain states, clinical experience and the available literature suggests that it has an important role to play, provided that it is used in the context of a multidisciplinary approach, with a preparedness to be flexible, within a time-limited framework and with a research and evaluative component built in whenever possible and practicable.