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Pain Med. 2008 Mar 11

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Pregabalin in the Treatment of Refractory Neuropathic Pain: Results of a 15-Month Open-Label Trial.

Stacey BR, Dworkin RH, Murphy K, Sharma U, Emir B, Griesing T.

Departments of Comprehensive Pain Center, Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon, USA.

Objective. Neuropathic pain associated with postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN) can be intractable and may not respond to commonly used treatments, such as tricyclic antidepressants (TCAs) and opioids. This long-term, open-label study was a preliminary evaluation of pregabalin for patients whose pain had been judged refractory to other treatments for neuropathic pain. Design. Patients had previously participated in double-blind, placebo-controlled, randomized trials of pregabalin in DPN and PHN. They had moderate to severe neuropathic pain despite treatment with gabapentin, a TCA, and a third medication (e.g., other anticonvulsants, opioid, selective serotonin reuptake inhibitor, tramadol). Flexible-dosage pregabalin 150-600 mg/day was taken for 3-month periods followed by 3- to 28-day pregabalin "drug holidays," with an analysis up to 15 months (five treatment cycles). Pain intensity was measured using the visual analog scale of the Short-Form McGill Pain Questionnaire. Results. In total, 81 patients were included in this analysis. Pregabalin 150-600 mg/day was associated with clinically meaningful and sustained pain reduction during each treatment cycle. During pregabalin "drug holidays," pain quickly returned to baseline levels; it was reduced again when pregabalin was reinstated. Conclusions. These results suggest that pregabalin may be beneficial in patients with neuropathic pain who have had an unsatisfactory response to treatment with other medications.

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Anaesthesist. 2008 Mar 20 [Epub ahead of print]

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[Drugs for postoperative analgesia: routine and new aspects : Part 1: Non-opioids.]

[Article in German]

Jage J, Laufenberg-Feldmann R, Heid F.

Klinik für Anästhesiologie, Johannes Gutenberg-Universität, Langenbeckstr. 1, 55131, Mainz, Deutschland, juergen.jage@ukmainz.de.

In part 1 of this review the perioperative aspects of the use of non-opioids (acetaminophen, dipyrone, traditional NSAR, coxibs) and in part 2 of opioids (weak opioids: tramadol, tilidine with naloxone, strong opioids: morphine, piritramide, oxycodone, hydromorphone, fentanyl, methadone, buprenorphine) and coanalgesics (gabapentinoids, ketamine) will be discussed. The main aim is to describe the relationship between analgesic efficacy and side effects to make clinical decisions easier in patients with preoperative renal, gastrointestinal, cardiovascular and other diseases. Some new aspects concerning perioperative administration of gabapentinoids and ketamine in patients with perioperative neuropathic pain are discussed.

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Neuroimage. 2007;37 Suppl 1:S80-8. Epub 2007 Apr 10. Links

Brain imaging of neuropathic pain.

Moisset X, Bouhassira D.

INSERM U-792, Centre de Traitement et d'Evaluation de la Douleur, CHU Ambroise Pare, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt cedex, France.

Many studies have focused on defining the network of brain structures involved in normal physiological pain. The different dimensions of pain perception (i.e., sensory discriminative, affective/emotional, cognitive/evaluative) have been shown to depend on different areas of the brain. In contrast, much less is known about the neural basis of pathological chronic pain. In particular, it is unclear whether such pain results from changes to the physiological "pain matrix". We review here studies on changes in brain activity associated with neuropathic pain syndromes-a specific category of chronic pain associated with peripheral or central neurological lesions. Patients may report combinations of spontaneous pain and allodynia/hyperalgesia-abnormal pain evoked by stimuli that normally induce no/little sensation of pain. Modern neuroimaging methods (positron emission tomography (PET) and functional MRI (fMRI)) have been used to determine whether different neuropathic pain symptoms involve similar brain structures and whether these structures are related to the physiological "pain matrix". PET studies have suggested that spontaneous neuropathic pain is associated principally with changes in thalamic activity and the medial pain system, which is preferentially involved in the emotional dimension of pain. Both PET and fMRI have been used to investigate the basis of allodynia. The results obtained have been very variable, probably reflecting the heterogeneity of patients in terms of etiology, lesion topography, symptoms and stimulation procedures. Overall, these studies indicated that acute physiological pain and neuropathic pain have distinct although overlapping brain activation pattern, but that there is no unique "pain matrix" or "allodynia network".

PMID: 17512757 [PubMed - indexed for MEDLINE]

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J Opioid Manag. 2006 May-Jun;2(3):147-53. Links

Opioids and brain imaging.

Balasubramanian S, Morley-Forster P, Bureau Y.

Interdisciplinary Pain Program, Schulich School of Medicine, St. Joseph's Health Care London, Ontario, Canada.

Since the introduction of the gate-control theory, a plethora of evidence to support the spinal processing of pain signals has come to light. Cognitive and affective aspects of the pain experience indicate the importance of supraspinal structures, but the biological mechanisms have remained inadequately explored. Within the past decade, imaging techniques have emerged that enable in vivo assessment of the central opioidergic system and the central processing of pain. The two most important imaging modalities to this end are functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). This article will describe the underlying principles of these techniques and explain their importance in determining the loci of opioidergic pathways and their neuromodulatory influence on acute and chronic pain conditions, role in placebo effects, implication in drug dependence, and potential role in studying the analgesic efficacy of new drugs.

PMID: 17319448 [PubMed - indexed for MEDLINE]

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Med Hypotheses. 2007;68(3):506-11. Epub 2006 Oct 30. Links

Chronic pain: a non-use disease.

Pruimboom L, van Dam AC.

Faculty of Human Sciences, University of Gerona, C/Francesc Masia 65 Salt, Spain. leo.pruimboom@fudgif.udg.es

One of the major problems in modern medicine is to find remedies for the group of people with chronic pain syndromes. Low back pain is one of the most frequent syndromes and perhaps the most invalidating of all of them. Chronic pain seems to develop through several pathways affecting the spinal cord and the brain: (1) neuro-anatomical reorganisation, (2) neuro-physiological changes, and (3) activation of glia cells (immune reaction in the central nervous system). Although all of these pathways seem to provide a (partial) plausible explanation for chronic pain, treatments influencing these pathways often fail to alleviate chronic pain patients. This could be because of the probability that chronic pain develops by all three mechanisms of disease. A treatment influencing just one of these mechanisms can only be partially successful. Other factors that seem to contribute to the development of chronic pain are psychosocial. Fear, attention and anxiety are part of the chronic pain syndrome being cause or consequence. The three pathways and the psycho-emotional factors constitute a psycho-neuro-immunological substrate for chronic pain syndromes; a substrate which resembles the substrate for phantom pain and functional invalidity after stroke. Both phantom pain and functional invalidity are considered non-use syndromes. The similarity of the substrate of both these two neurological disorders and chronic pain makes it reasonable to consider chronic pain a non-use disease (the hypothesis). To test this hypothesis, we developed a "paradoxal pain therapy". A therapy which combines the constraint induced movement therapy and strategies to dissociate pain from conditioning factors like fear, anxiety and attention. The aim of the therapy is to establish a behaviour perpendicular on the pathological pain-behaviour. Clinically, the treatment seems promising, although we just have preliminary results. Further clinical and laboratory studies are needed to measure eventual changes at neuro-anatomical and neuro-psychological level using modern neuro-imaging instruments (PET, SPECT, fMRI). Randomised clinical trials should be carried out to test our hypothesis for all-day use in clinical practice. The hypothesis: chronic pain is a non-use disease produced by psycho-emotional factors like fear, attention and anxiety. Optimal treatment should be based on physiological use, and dissociation of pain and the mentioned psycho-emotional factors. Paradoxal pain therapy could serve these treatment conditions.

PMID: 17071012 [PubMed - indexed for MEDLINE]

Anesth Analg. 2008 Feb;106(2):628-37, table of contents.

Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial.

Wallace MS, Rauck R, Fisher R, Charapata SG, Ellis D, Dissanayake S; Ziconotide 98-022 Study Group.

Center for Pain Medicine, University of California, San Diego, La Jolla, California 92093, USA. mswallace@ucsd.edu

BACKGROUND: Ziconotide is a non-opioid drug indicated for management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatments. METHODS: Six-hundred and forty-four patients with severe chronic pain participated in this open-label, multicenter study. Ziconotide titration was followed by long-term infusion. Efficacy assessments included the Visual Analog Scale of Pain Intensity. Safety was assessed via adverse events (AEs), vital signs, and routine laboratory values. RESULTS: One-hundred and nineteen patients received ziconotide for > or = 360 days; total exposure was 350.9 patient years. Median duration of ziconotide therapy was 67.5 days (range, 1.2-1215.5 days); mean dose at last infusion was 8.4 microg/d (range, 0.048-240.0 microg/d). Median Visual Analog Scale of Pain Intensity scores at baseline, month 1, and the last available observation up to month 2 were 76 mm (range, 4-100 mm), 68 mm (range, 0-100 mm), and 73 mm (range, 0-100 mm), respectively. Most patients (99.7%) experienced > or = 1 AE. Most AEs were of mild (43.5%) or moderate (42.3%) severity; 58.6% of AEs were considered unrelated to ziconotide. The most commonly reported AEs (> or = 25% of patients) included nausea, dizziness, headache, confusion, pain, somnolence, and memory impairment. Clinically significant abnormalities (> 3 times the upper limit of normal) in creatine kinase levels were reported in 0.9% of patients at baseline, 5.7% at month 1, and 3.4% at ziconotide discontinuation. No drug-related deaths, IT granulomas, or permanent adverse sequelae occurred with ziconotide therapy. CONCLUSION: We conclude that long-term IT ziconotide is an option for patients with severe, refractory chronic pain.

Publication Types: Clinical Trial Comparative Study Multicenter Study Research Support, Non-U.S. Gov't

PMID: 18227325 [PubMed - indexed for MEDLINE]

The Relation of Post-Traumatic Stress Symptoms to Depression and Pain in Patients With Accident-Related Chronic Pain.

Roth RS, Geisser ME, Bates R.

Department of Physical Medicine and Rehabilitation, University of Michigan Health System, Ann Arbor, Michigan.

Symptoms of post-traumatic stress disorder (PTSD) are a common comorbidity in patients with a history of accident-related chronic pain and depression. However, little is known regarding the influence of PTSD in contributing to the affective distress, pain experience, and disability associated with chronic pain in this population. This study used structural equation modeling to examine 3 models that assess these relations in a sample of chronic pain patients with accident-related pain. Subjects were assessed for pain experience, depressive symptoms, anxiety, PTSD symptoms, pain disability, and relevant demographic variables. Pearson correlations indicated that symptoms of depression were significantly related to more severe pain, disability, and PTSD symptoms. PTSD symptoms were significantly associated with higher disability. The model of best fit indicated that after controlling for the influence of anxiety on the dependent measures, PTSD symptoms have a direct influence on severity of depressive symptoms, whereas depressive symptoms have a direct influence on pain intensity and an indirect impact on pain intensity by way of their effect on disability. These data point to the importance of unresolved PTSD symptoms in contributing to the level of depression, pain, and disability exhibited by chronic pain patients and highlight the need to consider directed and primary treatment of PTSD in pain rehabilitation programs. PERSPECTIVE: This study highlights the impact of symptoms of PTSD on levels of depression, disability, and pain in patients with pain secondary to physical injury. Our results suggest that pain rehabilitation programs provide directed interventions for PTSD symptoms among this population to improve pain treatment outcomes.

PMID: 18343728 [PubMed - as supplied by publisher]

Eur Psychiatry. 2008 Mar 5 [Epub ahead of print]

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Change in pain severity with open label venlafaxine use in patients with a depressive symptomatology: An observational study in primary care.

Begré S, Traber M, Gerber M, von Känel R.

Department of General Internal Medicine, Division of Psychosomatic Medicine, University Hospital/Inselspital, CH-3010 Bern, Switzerland.

PURPOSE: Venlafaxine has shown benefit in the treatment of depression and pain. Worldwide data are extensively lacking investigating the outcome of chronic pain patients with depressive symptoms treated by venlafaxine in the primary care setting. This observational study aimed to elucidate the efficacy of venlafaxine and its prescription by Swiss primary care physicians and psychiatrists in patients with chronic pain and depressive symptomatology. SUBJECTS AND METHODS: We studied 505 patients with depressive symptoms suffering from chronic pain in a prospective naturalistic Swiss community based observational trial with venlafaxine in primary care. These patients have been treated with venlafaxine by 122 physicians, namely psychiatrists, general practitioners, and internists. RESULTS: On average, patients were treated with 143+/-75mg (0-450mg) venlafaxine daily for a follow-up of three months. Venlafaxine proved to be beneficial in the treatment of both depressive symptoms and chronic pain. DISCUSSION: Although side effects were absent in most patients, physicians might have frequently omitted satisfactory response rate of depression by underdosing venlafaxine. Our results reflect the complexity in the treatment of chronic pain in patients with depressive symptoms in primary care. CONCLUSION: Further randomized dose-finding studies are needed to learn more about the appropriate dosage in treating depression and comorbid pain with venlafaxine.

PMID: 18328675 [PubMed - as supplied by publisher]

Plast Reconstr Surg. 2008 Mar;121(3):908-14; discussion 915-7.

The role of peripheral nerve surgery in the treatment of chronic pain associated with amputation stumps.

Ducic I, Mesbahi AN, Attinger CE, Graw K.

Department of Plastic Surgery, Georgetown University Medical Center, Washington, DC 20007, USA. ducici@gunet.georgetown.edu

BACKGROUND: Debilitating pain following amputation surgery can seriously affect the long-term success of the operation and the patient's quality of life. Often, such patients are unable to ambulate because of pain when using a prosthesis; become grouped in the chronic pain category; and are treated with high-dose narcotics, antidepressants, or other methods to treat symptoms that may provide little or no relief. Little attention has been given to the role of peripheral nerve surgery as an early treatment option. METHODS: A retrospective review of 21 consecutive amputees with chronic stump pain was performed. The surgical technique included removal of the neuroma with implantation of the proximal nerve ending into adjacent muscle. In addition to the surgical outcome, other variables evaluated included resolution or optimal improvement in pain and spasms, change in quality of life, and ambulation status. RESULTS: The mean duration of stump pain before surgery was 7.28 months (range, 5 to 18 months). After surgery, there were statistically significant changes with pain and spasms, quality-of-life, and ambulation status. The mean follow-up was 22.8 months, and there was no recurrence of neuroma. CONCLUSIONS: Peripheral nerve surgery plays a significant role in the treatment of chronic pain associated with amputation stumps. After conservative treatment methods have been exhausted, a treatment algorithm for peripheral nerve surgery is successful in improving or resolving chronic pain and the quality-of-life issues associated with amputation patients.

PMID: 18317139 [PubMed - indexed for MEDLINE]

Pain. 2007 Jan;127(1-2):183-94. Epub 2006 Nov 29. Links

Differential brain opioid receptor availability in central and peripheral neuropathic pain.

Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L.

INSERM EMI 342 (Central Integration of pain), 59 Bd PINEL, 69394 Lyon & St. Etienne, France. joseph.maarrawi@chu-lyon.fr

This study used positron emission tomography (PET) and [11C]diprenorphine to compare the in vivo distribution abnormalities of brain opioid receptors (OR) in patients with peripheral (n=7) and central post-stroke pain (CPSP, n=8), matched for intensity and duration. Compared with age- and sex-matched controls, peripheral neuropathic pain (NP) patients showed bilateral and symmetrical OR binding decrease, while in CPSP binding decrease predominated in the hemisphere contralateral to pain. In CPSP patients, interhemispheric comparison demonstrated a significant decrease in opioid binding in posterior midbrain, medial thalamus and the insular, temporal and prefrontal cortices contralateral to the painful side. Peripheral NP patients did not show any lateralised decrease in opioid binding. Direct comparison between the central and peripheral groups confirmed a significant OR decrease in CPSP, contralateral to pain. While bilateral binding decrease in both NP groups may reflect endogenous opioid release secondary to chronic pain, the more important and lateralised decrease specific to CPSP suggests opioid receptor loss or inactivation in receptor-bearing neurons. Opioid binding decrease was much more extensive than brain anatomical lesions, and was not co-localised with them; metabolic depression (diaschisis) and/or degeneration of OR neurons-bearing secondary to central lesions appears therefore as a likely mechanism. Central and peripheral forms of NP may differ in distribution of brain opioid system changes and this in turn might underlie their different sensitivity to opiates.

PMID: 17137714 [PubMed - indexed for MEDLINE]

Acta Anaesthesiol Scand. 2008 Mar;52(3):327-31.

Chronic pain after hysterectomy.

Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS.

Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark. birgitte.brandsborg@ki.au.dk

BACKGROUND: Chronic pain is a well-known adverse effect of surgery, but the risk of chronic pain after gynaecological surgery is less established. METHOD: This review summarizes studies on chronic pain following hysterectomy. The underlying mechanisms and risk factors for the development of chronic post-hysterectomy pain are discussed. RESULTS AND CONCLUSION: Chronic pain is reported by 5-32% of women after hysterectomy. A guideline is proposed for future prospective studies.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 18269384 [PubMed - in process]

Hernia. 2007 Nov 20 [Epub ahead of print]

Chronic pain after Kugel inguinal hernia repair.

Hompes R, Vansteenkiste F, Pottel H, Devriendt D, Van Rooy F.

Department of Abdominal Surgery, AZ Groeninge, Campus St-Niklaas, Houtmarkt 33, 8500, Kortrijk, Belgium, roelhompes@gmail.com.

BACKGROUND: The incidence of chronic pain after Kugel herniorrhaphy is not well documented, since it was not used as a primary outcome measure in studies reporting on the Kugel technique. The aim of the present study was to report on the incidence and severity of chronic pain 1 year after Kugel herniorrhaphy and to identify the risk factors associated with the development of chronic pain. METHODS: The study population comprised all patients in our teaching hospital who underwent a Kugel inguinal hernia repair between January 2002 and June 2005. Postoperative complications, analgesia consumption and postoperative functional impairment were recorded during an outpatient clinic after 4-6 weeks. Chronic pain and cutaneous sensory changes were followed-up by means of a telephone questionnaire 1 year after surgery. RESULTS: After 1 year, 57 (15.1%) of 377 patients complained of mild to moderate pain. The incidence of mild and moderate chronic pain was 14.3 and 0.8%, respectively. None of the patients had severe chronic pain. Only one patient reported numbness in the groin area. Age and immediate postoperative pain were significant risk factors associated with chronic pain after Kugel inguinal herniorrhaphy. Although the difference was not significant, female patients seemed to be more prone to develop chronic pain. CONCLUSIONS: The Kugel inguinal hernia repair is associated with a low rate of postoperative chronic pain. The minimally invasive preperitoneal approach of the Kugel technique probably causes less nerve damage and subsequent neuropathic pain. Chronic pain seems to be more common in young female patients with immediate postoperative pain.

PMID: 18026896 [PubMed - as supplied by publisher]

Pharmacotherapy. 2007 Nov;27(11):1571-87.

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Antidepressant agents for the treatment of chronic pain and depression.

Jann MW, Slade JH.

Department of Pharmacy Practice, Mercer University College of Pharmacy and Health Sciences, 3001 Mercer University Drive, Atlanta, GA 30341, USA. jann_mw@mercer.edu

Depression and painful somatic symptoms commonly occur together. Depression and chronic pain can have devastating effects on a patient's health, productivity, and overall quality of life. When moderate-to-severe pain exists, it can impair patient function while making treatment more difficult or resistant, with increased severity in depressive symptoms and worse outcomes. A variety of chronic pain syndromes exist, including diabetic neuropathy. A high prevalence of patients with chronic pain display depressive symptoms. Treatment for these conditions relies on pharmacologic therapy coupled with diligent, periodic assessments of changes in symptom severity. The link between pain and depression lies in the central and peripheral nervous systems. The brain stem serves as an important connection between the higher brain centers and the spinal cord. In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.

Publication Types:

Review

PMID: 17963465 [PubMed - indexed for MEDLINE]

Int J Geriatr Psychiatry. 2007 Nov 27 [Epub ahead of print]

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Chronic pain and depression among geriatric psychiatry inpatients.

Meeks TW, Dunn LB, Kim DS, Golshan S, Sewell DD, Atkinson JH, Lebowitz BD.

Department of Psychiatry, Division of Geriatric Psychiatry, University of California, San Diego, CA, USA.

OBJECTIVES: We examined whether chronic pain among depressed geriatric inpatients was associated with several clinical variables-comorbid psychiatric and medical diagnoses, length of hospitalization, suicidal ideation, and sleep duration. METHODS: Medical charts of inpatients admitted to a geriatric psychiatry unit over 2 years were examined retrospectively; 148 patients with a depressive disorder were identified. Admission pain assessments were used to classify whether patients had chronic pain. Other variables of interest were collected from charts. RESULTS: 62% of patients reported chronic pain. In multivariate regression analysis, depressed older adults with chronic pain were more likely to report suicidal ideation, be diagnosed with personality disorder, have higher medical burden, and experience decreased total sleep time compared to depressed older adults without chronic pain. CONCLUSIONS: Chronic pain-common in depressed older adults-may influence clinical features of depression and should be assessed as a possible suicide risk factor. Prospective studies should examine causal relationships and determine the effects of adequate pain treatment on depression course and suicide risk in older adults. Copyright (c) 2007 John Wiley & Sons, Ltd.

PMID: 18041102 [PubMed - as supplied by publisher]

Eur J Pain. 2008 Apr;12(3):378-84. Epub 2007 Sep 17.

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Comparison of epidural analgesia and intercostal nerve cryoanalgesia for post-thoracotomy pain control.

Ju H, Feng Y, Yang BX, Wang J.

Department of Anesthesiology, Peking University People's Hospital, 11 Xi Zhimen South Street, Beijing 100044, PR China.

Epidural analgesia is regarded as the gold method for controlling post-thoracotomy pain. Intercostal nerve cryoanalgesia can also produce satisfactory analgesic effects, but is suspected to increase the incidence of chronic pain. However, randomized controlled trials comparing these two methods for post-thoracotomy acute pain analgesic effects and chronic pain incidents have not been conducted previously. We studied 107 adult patients, allocated randomly to thoracic epidural bupivacaine and morphine or intercostal nerve cryoanalgesia. Acute pain scores and opioid-related side effects were evaluated for three postoperative days. Chronic pain information, including the incidence, severity, and allodynia-like pain, was acquired on the first, third, sixth and twelfth months postoperatively. There was no significant difference on numeral rating scales (NRS) at rest or on motion between the two groups during the three postoperative days. The patient satisfaction results were also similar between the groups. The side effects, especially mild pruritus, were reported more often in the epidural group. Both groups showed high incidence of chronic pain (42.1-72.1%), and no significance between the groups. The incidence of allodynia-like pain reported in cryo group was higher than that in Epidural group on any postoperative month, with significance on the sixth and the twelfth months postoperatively (P<0.05). More patients rated their chronic pain intensity on moderate and severe in cryo group and interfered with daily life (P<0.05). Both thoracic epidural analgesia and intercostal nerve cryoanalgesia showed satisfactory analgesia for post-thoracotomy acute pain. The incidence of post-thoracotomy chronic pain is high. Cryoanalgesia may be a factor that increases the incidence of neuropathic pain.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 17870625 [PubMed - in process]

Am J Surg. 2007 Sep;194(3):394-400.

Related Articles, Links

Chronic pain after mesh repair of inguinal hernia: a systematic review.

Nienhuijs S, Staal E, Strobbe L, Rosman C, Groenewoud H, Bleichrodt R.

Department of Surgery, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands. s.nienhuijs@hccnet.nl

BACKGROUND: Chronic pain is a severe complication of mesh-based inguinal hernia repair. Its perceived risk varies widely in the literature. The current objectives are to review the incidence, severity, and consequences of chronic pain and its etiologies. DATA SOURCES: A multi-database systematic search was conducted for prospective trials on mesh-based inguinal hernia repair reporting the measurement and outcome of pain at least 3 months postoperatively with a minimum follow-up of 80%. CONCLUSIONS: After mesh-based inguinal hernia repair, 11% of patients suffer chronic pain. More than a quarter of these patients have moderate to severe pain, mostly with a neuropathic origin. As a consequence of chronic pain, almost one third of patients have limitations in daily leisure activities. Chronic pain is less frequent after endoscopic repair and with the use of a light-weighted mesh.

Publication Types:

Review

PMID: 17693290 [PubMed - indexed for MEDLINE]

Schmerz. 2007 Aug;21(4):359-70; quiz 371-2.

Related Articles, Links

HOME

Ricerca Articoli su Internet

Ultimo aggiornamento Marzo 2008

NEWSLETTER

Articoli selezionati dalla letteratura internazionale sul Dolore Cronico

Pain Med. 2008 Mar 11

Related Articles, Links

---------------------------------------------------------------------------------------------------------------------------------

Anaesthesist. 2008 Mar 20 [Epub ahead of print]

Related Articles, Links

Neuroimage. 2007;37 Suppl 1:S80-8. Epub 2007 Apr 10. Links

Brain imaging of neuropathic pain.

Moisset X, Bouhassira D.

INSERM U-792, Centre de Traitement et d'Evaluation de la Douleur, CHU Ambroise Pare, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt cedex, France.

PMID: 17512757 [PubMed - indexed for MEDLINE]

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J Opioid Manag. 2006 May-Jun;2(3):147-53. Links

Opioids and brain imaging.

Balasubramanian S, Morley-Forster P, Bureau Y.

Interdisciplinary Pain Program, Schulich School of Medicine, St. Joseph's Health Care London, Ontario, Canada.

PMID: 17319448 [PubMed - indexed for MEDLINE]

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Med Hypotheses. 2007;68(3):506-11. Epub 2006 Oct 30. Links

Chronic pain: a non-use disease.

Pruimboom L, van Dam AC.

Faculty of Human Sciences, University of Gerona, C/Francesc Masia 65 Salt, Spain. leo.pruimboom@fudgif.udg.es

PMID: 17071012 [PubMed - indexed for MEDLINE]

Anesth Analg. 2008 Feb;106(2):628-37, table of contents.

Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial.

Wallace MS, Rauck R, Fisher R, Charapata SG, Ellis D, Dissanayake S; Ziconotide 98-022 Study Group.

Center for Pain Medicine, University of California, San Diego, La Jolla, California 92093, USA. mswallace@ucsd.edu

Publication Types: Clinical Trial Comparative Study Multicenter Study Research Support, Non-U.S. Gov't

PMID: 18227325 [PubMed - indexed for MEDLINE]

The Relation of Post-Traumatic Stress Symptoms to Depression and Pain in Patients With Accident-Related Chronic Pain.

Eur Psychiatry. 2008 Mar 5 [Epub ahead of print]

Related Articles, Links

Plast Reconstr Surg. 2008 Mar;121(3):908-14; discussion 915-7.

Pain. 2007 Jan;127(1-2):183-94. Epub 2006 Nov 29. Links

Differential brain opioid receptor availability in central and peripheral neuropathic pain.

Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L.

INSERM EMI 342 (Central Integration of pain), 59 Bd PINEL, 69394 Lyon & St. Etienne, France. joseph.maarrawi@chu-lyon.fr

PMID: 17137714 [PubMed - indexed for MEDLINE]

Acta Anaesthesiol Scand. 2008 Mar;52(3):327-31.

Research Support, Non-U.S. Gov't

PMID: 18269384 [PubMed - in process]

Hernia. 2007 Nov 20 [Epub ahead of print]

Pharmacotherapy. 2007 Nov;27(11):1571-87.

Related Articles, Links

Review

PMID: 17963465 [PubMed - indexed for MEDLINE]

Int J Geriatr Psychiatry. 2007 Nov 27 [Epub ahead of print]

Related Articles, Links

Eur J Pain. 2008 Apr;12(3):378-84. Epub 2007 Sep 17.

Related Articles, Links

Research Support, Non-U.S. Gov't

PMID: 17870625 [PubMed - in process]

Am J Surg. 2007 Sep;194(3):394-400.

Related Articles, Links

Review

PMID: 17693290 [PubMed - indexed for MEDLINE]

Schmerz. 2007 Aug;21(4):359-70; quiz 371-2.

Related Articles, Links

[Cancer pain management. Basic therapy and treatment of breakthrough pain]

[Article in German]

Nauck F, Eulitz N.

Abteilung Palliativmedizin, Georg-August-Universität Göttingen,Universitätsmedizin Göttingen, Deutschland. Friedemann.Nauck@med.uni-goettingen.de

Cancer pain imposes a great burden on patients and results in considerable constraints limiting their quality of life. The basic treatment for chronic pain consists in oral administration of long-acting preparations of various analgesic agents according to a set schedule. In addition to chronic pain, however, about 60% of cancer patients also suffer from breakthrough pain. Rapid-onset and short-acting preparations of highly potent opioids are available for the management of these attacks. To choose the correct analgesic agent, it is essential to take a comprehensive medical history and be aware of the different forms of pain present.

Publication Types:

PMID: 17684772 [PubMed - indexed for MEDLINE]

Chronic Pain Management

Role of Newer Antidepressants and Anticonvulsants Darrell Hulisz, RPh, PharmD Associate Professor of Family Medicine Case Western Reserve University School of Medicine, Cleveland, Ohio Associate Clinical Professor of Pharmacy Practice, Ohio Northern University College of Pharmacy, Ada, Ohio

Nicole Moore, PharmD candidate Ohio Northern University Pharmacy Intern, University Family Medicine Foundation, Cleveland, Ohio

US Pharm. 2007;32(5):55-61.

Chronic pain--pain that lasts longer than three to six months--affects over 75 million Americans, making it one of the most common and debilitating health problems in the United States today. 1 Although chronic pain is a common reason for seeking medical care, it is often undertreated, and patients may be exposed to potentially toxic and/or addictive side effects of currently available medications. Treatment failure may lower patients' quality of life and increase their economic burden. 2 Providing adequate analgesia for patients with moderate to severe pain may require the use of multiple medications, often at high dosages. This can lead to unwanted adverse effects, which can become intolerable for some patients. Chronic use of systemic NSAIDs is associated with multiple adverse effects, including gastrointestinal upset, gastric ulcer formation, renal dysfunction, and increased cardiovascular risk. While the use of opiate narcotics and related analgesics may be helpful for acute pain, chronic use of these medications can lead to dependence and/or abuse. Opiate drugs produce sedation, tolerance, constipation, and allergic and pseudoallergic reactions.

Due to a high rate of suboptimal treatment response and unwanted side effects from these medications, clinicians are seeking alternative therapy to manage chronic pain. New research has led to a better understanding of the pathophysiology and mechanisms of pain transmission, suggesting the possibility of using alternative drug classes to treat chronic pain.1,2 Two major drug classes being increasingly used to treat chronic pain are antidepressants and anticonvulsants. Thus, this article examines the evidence for using these drugs as treatment for nonmalignant chronic pain.

Mechanism of Pain The process of pain transmission involves many neural pathways and neurotransmitters within the central and peripheral nervous systems. An external stimulus activates pain receptors (also known as nociceptors), which produce an action potential that is transmitted to the spinal cord along afferent nerve fibers. These nerve fibers are classified according to the type of pain they transmit. Sharp, well-localized pain is transmitted along Ad nerve fibers, whereas dull, aching, poorly localized pain travels along C nerve fibers. The action potential then travels to the dorsal horn of the spinal cord where pain neurotransmitters, such as glutamate and substance P, are released. The transmission then continues up the spinal cord via ascending pathways to higher areas of the brain where pain is consciously experienced. Once the brain senses the painful stimulus, it releases inhibitory stimuli through the descending pathways back to the spinal cord to inhibit the sensation of pain. The modulation of pain is achieved through a variety of neurotransmitters, including endogenous opioids, serotonin (5-HT), norepinephrine (NE), and g -aminobutyric acid (GABA).3 The role of these inhibitory neurotransmitters has led to the rationale of using antidepressants and anticonvulsants to treat chronic pain.

Pain can be divided into two categories: nociceptive and neuropathic. Nociceptive pain is more commonly known as acute pain and is further categorized as somatic and visceral pain. Somatic pain usually arises from muscle or tissue injury. It is well localized and is often described as aching, throbbing, or shooting sensations. Visceral pain is often referred from an internal organ. This type of pain is usually treated with traditional pain medications, such as opioids and NSAIDs.3

Neuropathic pain is mechanistically different from nociceptive pain, warranting different pharmacologic agents for treatment. The mechanism of neuropathic pain is more complex and not as well understood as that of nociceptive pain. It is theorized that neuropathic pain occurs as a result of dysfunction of or damage to both the central and peripheral nervous systems.4 The malfunction in the central nervous system (CNS) can lead to several different processes (e.g., increased cell firing, decreased inhibition of neuronal activity, and sensitization) that are responsible for chronic pain. Neuropathic pain is often described as burning, shooting, tingling, and possibly accompanied by numbness. Hyperalgesia (the exaggerated response to normally noxious stimuli) and allodynia (the painful response to a normally nonpainful stimulus) often occur in neuropathic pain syndromes. Chronic pain can present as a manifestation of both nociceptive and neuropathic pain, suggesting a combined pharmacologic approach for optimal treatment.3-5

Antidepressants Antidepressants have been used for many years to treat pain. Historically, the most common class of antidepressants used to treat chronic pain is the tricyclic antidepressants (TCAs), such as amitriptyline. Other drugs included in this class are nortriptyline, desipramine, and imipramine. Their role in pain modulation correlates with their ability to increase the amount of circulating inhibitory pain neurotransmitters, NE and 5-HT, through reuptake inhibition. 6 The analgesic activity of TCAs likely occurs independently of their antidepressant activity.6 This theory is supported by both the smaller dosages needed to achieve analgesia and the faster time for analgesic response in comparison to their antidepressant effects (days versus weeks). Their efficacy in the treatment of neuropathic pain syndromes is supported by several review articles.7,8 The utility of TCAs in the treatment of neuropathic pain is limited by their tolerability. Not only do they act on NE and 5-HT receptors, but they also act on histamine and muscarinic receptors, which causes unwanted anticholinergic side effects (e.g., sedation, dry mouth, blurred vision, and urinary retention). Due to their unfavorable side-effect profile, researchers have turned to new classes of antidepressants for the treatment of chronic pain syndromes, specifically duloxetine, a dual reuptake inhibitor.

Duloxetine (Cymbalta) was approved by the FDA in 2004 for the treatment of depression and diabetic peripheral neuropathy (DPN). Duloxetine works similarly to TCAs by inhibiting the reuptake of both norepinephrine and serotonin but differs in that it does not affect histamine or muscarinic receptors. Thus, the anticholinergic side effects commonly seen with TCAs are not present with duloxetine. Compared to other dual reuptake inhibitors, such as venlafaxine (Effexor), duloxetine differs by its balanced affinity between NE and 5-HT receptors. Venlafaxine is predominantly selective for 5-HT at lower dosages and has increased NE affinity as dosages increase. Clinical studies have shown duloxetine to be an effective treatment for DPN with dosages of 60 mg once daily.9

Wernicke et al. studied the efficacy of duloxetine in DNP in dosages of 60 mg daily and 60 mg twice daily versus placebo.9 The primary outcome tested was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. At the end of week 1 through week 12, both duloxetine 60 mg daily and 60 mg twice daily led to a significant decrease in pain severity versus placebo (P <.001), with no significant difference between the two active treatment groups.

There is also evidence supporting the use of duloxetine for the treatment of fibromyalgia.10 Arnold et al. conducted a 12-week, randomized, double-blind, placebo-controlled trial to assess the efficacy of duloxetine in 354 women who had fibromyalgia. Patients were randomized into three treatment groups: duloxetine 60 mg once daily, duloxetine 60 mg twice daily, and placebo. The primary outcome was the Brief Pain Inventory average pain score and response to treatment, defined as less than a 30% reduction in the pain score. At 12 weeks, a significantly higher percentage of participants in the duloxetine group had a reduction of 30% or more in their pain symptoms (P <.001 for 60 mg once daily; P <.002 for 60 mg twice daily). There was no significant difference in pain response between duloxetine 60 mg once daily and 60 mg twice daily. The most common side effects seen with duloxetine included somnolence, nausea, dry mouth, decreased appetite, and constipation. Patients taking duloxetine 60 mg twice daily experienced more somnolence, jitteriness, and nervousness. Both treatment groups experienced slight increases in alkaline phosphatase. There were no statistically significant changes in blood pressure in either treatment group.

To reduce the side effects associated with duloxetine, treatment can be initiated at lower dosages (e.g., 20 mg/day) and titrated on a weekly basis to achieve the desired therapeutic effect. If chronic treatment is discontinued, it must be gradually tapered, rather than stopped abruptly. Duloxetine is a moderate inhibitor of the cytochrome P450 (CYP) 2D6 isoenzyme and a substrate for both CYP2D6 and 1A2 isoenzymes. Duloxetine should be used with caution when coadministering drugs that may inhibit or induce CYP2D6 and 1A2. Duloxetine is available in 20-, 30-, and 60-mg capsules. Compared to TCAs, an advantage of duloxetine is better tolerability; however, disadvantages include higher cost and lack of long-term safety data.

Although selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are first-line treatments for depression, their role in treating chronic pain is limited. This is most likely due to their sole activity on 5-HT receptors and lack of activity on NE receptors.8

Anticonvulsants Anticonvulsants, such as carbamazepine, gabapentin, and pregabalin, have also been used to treat neuropathic and other types of chronic pain. They exert their pharmacologic action at many different sites that may be involved in pain transmission. Possible mechanisms include inhibition of voltage-gated sodium and calcium channels, potentiation of GABA, and inhibition of glutamate receptors, all of which lead to decreased neuronal excitation and enhanced inhibition. Gabapentin (Neurontin) and pregabalin (Lyrica) are classified as second-generation anticonvulsants and are typically better tolerated and have fewer drug interactions than the first-generation anticonvulsants (e.g., carbamazepine).11,12 For this reason, the following discussion of anticonvulsants in the treatment of neuropathic pain is limited to gabapentin and pregabalin.

Gabapentin The popularity of gabapentin, initially indicated as adjuvant treatment for partial seizures, rose with its success in treating neuropathic pain. Studies have been conducted to assess the efficacy of gabapentin in neuropathic pain.13 According to a recent Cochrane Review of the use of gabapentin in the treatment of acute and chronic pain,13 the number needed to treat (NNT) for improvement in chronic pain is 4.3 (95% confidence interval [CI], 3.5–5.7). This review included all trials from 1998 to 2005 involving gabapentin as treatment for neuropathic pain. Categorized into individual neuropathies, the NNT for effective pain relief in diabetic neuropathy was 2.9 (95% CI, 2.2–4.3) and for post herpetic neuralgia (PHN), 3.9 (95% CI, 3.0–5.7). Gabapentin exerts its pharmacologic action by binding to the a 2d subunit of voltage-gated calcium channels. Studies show a relationship between the a2d Ca2+ channel and pain modulation.14 Although the mechanism is not fully understood, the binding of gabapentin to the a2d Ca2+ channel is thought to inhibit the release of excitatory neurotransmitters.14

Gabapentin was well tolerated in trials assessing its efficacy in neuropathic pain. The number needed to harm (NNH) for adverse events leading to trial withdrawal was not significant. The NNH for minor harm was 3.7 (95% CI, 2.4–5.4).13 The most common side effects associated with gabapentin were somnolence, dizziness, and ataxia. The dosage range for neuropathic pain is 1,800 to 3,600 mg/day in three divided doses. To lower the risk of side effects, the dosage should begin at 300 mg at bedtime and be titrated to 300 mg twice daily on day 2, then 300 mg three times daily on day 3. An adequate course of gabapentin should allow six to eight weeks for dosage titration and an additional one to two weeks at the maximum dosage. Gabapentin exhibits large interpatient variability; therefore, the dosages should be titrated based on tolerability and therapeutic effect. If the drug must be discontinued, it should be tapered over one week. Gabapentin is renally eliminated and should be used in reduced dosages for patients with renal insufficiency.

Pregabalin Pregabalin is the newest second-generation anticonvulsant approved by the FDA for use in DPN and PHN. Similar to gabapentin, pregabalin exerts its pharmacologic action by binding to the a2d subunit of voltage-gated calcium channels in the CNS, leading to the inhibition of excitatory neurotransmitter release.14 Dosages range from 300 to 600 mg/day depending on the treatment indication. In a randomized, placebo-controlled study of 173 patients conducted by Dworkin et al., pregabalin 300 to 600 mg /day led to a significantly higher proportion of patients receiving 50% or greater pain reduction in symptoms of PHN, compared to those receiving placebo (P =.001).15 Lesser and associates conducted a randomized, double-blind, placebo-controlled trial of 338 patients that assessed the efficacy of pregabalin in DPN.16 At dosages of 300 and 600 mg/day, there was a superior pain response in comparison to placebo (P =.0001), but no additional benefit was seen between the 300 mg/day and 600 mg/day groups. Aside from significant improvements in pain scores, both treatment groups experienced improvement in sleep. Data support pregabalin's efficacy in fibromyalgia as well. 17 In an eight-week randomized, double-blind, placebo-controlled trial (N = 529), pregabalin (450 mg/day) reduced the average severity of pain significantly, compared to placebo, in patients with fibromyalgia (P <.001).17 In the pregabalin treatment group, more patients achieved greater than a 50% improvement in pain, compared to placebo (P = .003). Treatment with pregabalin also improved prominent symptoms of fibromyalgia, including disordered sleep and fatigue.

Generally, pregabalin has been well tolerated in studies assessing its efficacy in pain syndromes. The most common side effects were somnolence and dizziness, which occurred more frequently at higher dosages. Peripheral edema, weight gain, headache, and blurred vision were side effects less commonly encountered. To reduce the incidence of side effects, initial treatment should begin at lower doses, such as 150 mg/day in two divided doses, and increased at weekly intervals to 300 to 600 mg/day based on tolerability and desired therapeutic effect. The drug dosage must be adjusted for patients with renal insufficiency (creatinine clearance < 60 mL/minute). If cessation of therapy is necessary, pregabalin should be slowly tapered over a week, rather than stopped abruptly.

Currently, no head-to-head trials have been conducted comparing gabapentin and pregabalin for the treatment of neuropathic pain. Pregabalin is FDA approved for both DPN and PHN, whereas gabapentin is approved only for the latter indication. Clinical studies have shown gabapentin to be effective in the treatment of DPN.13 When compared, pregabalin and gabapentin share the same desirable safety characteristics (e.g., no active metabolites, no significant drug interactions, and minimal side effects). Pregabalin may have some pharmacokinetic advantages over gabapentin. The plasma concentrations appear to be linear with increasing dosages; the dosing interval is twice daily versus three times daily with gabapentin; and there may be less interpatient variability in response than with gabapentin.14 While gabapentin is available in generic form, pregabalin is only available as the brand name Lyrica. A one-month supply of gabapentin 600 mg three times per day costs about $90, whereas a one-month supply of pregabalin 150 mg twice daily costs approximately $124.

Topical Therapy In patients with chronic pain that is more localized, patients at risk for adverse effects with systemic NSAIDs or opiates may benefit from local therapies. Novel topical nonsteroidal anti-inflammatory agents, such as diclofenac solution (Pennsaid) and diclofenac epolamine topical patch 1.3% (Flector), will soon be available in the U.S. Based on evidence from short-term clinical trials, topical diclofenac solution appears to be both efficacious and safe to use in patients with osteoarthritis of the knee.18,19 Other topical agents with proven efficacy for chronic pain include capsaicin cream and transdermal lidocaine.20,21

Conclusion Chronic pain continues to afflict millions of Americans daily. Current treatment options for chronic pain are often ineffective and limited by side effects, tolerance, and even addiction, leaving clinicians in need of better alternative drug classes. Certain antidepressants and anticonvulsants have been proven useful to treat chronic pain syndromes. Specifically, newer agents such as duloxetine, gabapentin, and pregabalin effectively treat pain with more favorable side-effect profiles, compared to TCAs and first-generation anticonvulsants.

Pharmacists should have knowledge of the multiple effective therapies available to treat patients with chronic nonmalignant pain, especially in those at risk for adverse effects from opiates and NSAIDs. Novel anticonvulsants and antidepressants are becoming first-line for neuropathic pain, such as diabetic neuropathy and PHN. Larger clinical trials are needed to establish their role in chronic musculoskeletal pain (e.g., osteoarthritis and fibromyalgia). Localized chronic pain may be treated with topical agents, such as capsaicin cream, transdermal lidocaine, and topical NSAIDs.

References 1. Forde G. Adjuvant analgesics for the treatment of neuropathic pain: evaluating efficacy and safety profiles. J Fam Pract. 2007;56:3-12. 2. Maizels M, McCarberg B. Antidepressants and antiepileptic drugs for chronic non-cancer pain. Am Fam Physician. 2005;71:483-490. 3. Bauman TJ. Pain management. In: Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiological Approach. 6th ed. New York, NY: McGraw-Hill; 2005:1089-1104. 4. Bolay H, Moskowitz MA. Mechanisms of pain modulation in chronic syndromes. Neurology. 2002;59(suppl 2):S2-S7. 5. Rowbotham MC. Mechanisms of neuropathic pain and their implications for the design of clinical trials. Neurology. 2005;65:S66-S73. 6. Mico JA, Ardid D, Berroscoso E, Eschalier A. Antidepressants and pain. Trends Pharmacol Sci . 2006;27:348-354. 7. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews. 2005(3). Art. No.: CD005454. DOI: 10.1002/14651858.CD005454. 8. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantative systematic review. J Pain Symptom Manage. 2000;20:449-458. 9. Wernicke JF, Pritchett YL, D'Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67:1431-1420. 10. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15. 11. Ettinger A, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurother. 2007;4:75-83. 12. Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005(3). Art. No.: CD001133. DOI: 10.1002/14651858.CD001133. 13. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005(3). Art. No.: CD005452. DOI: 10.1002/14651858.CD005452. 14. Dooley DJ, Taylor CP, Sonevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28:75-82. 15. Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo controlled trial. Neurology. 2003;60:1274-1283. 16. Lesser H, Sharma U, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a randomized controlled trial. Neurology. 2004;63:2104-2110. 17. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273. 18. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of topical diclofenac solution (Pennsaid®) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-2012. 19. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (Pennsaid®) in the treatment of primary osteoarthritis of the knee. Arch Intern Med. 2004;164:2017-2023. 20. Frerick H, Keitel W, Kuhn U, et al. Topical treatment of chronic low back pain with a capsicum plaster. Pain. 2003;106:59-64. 21. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev. 2003;55:1-20.

To comment on this article, contact editor@uspharmacist.com.

Acute Pain Pharmacotherapy

Scott A. Strassels, PharmD, PhD, BCPS Assistant Professor, Division of Pharmacy Practice, University of Texas, Austin, Texas

Ewan McNicol, PharmD, MS-PREP Tufts–New England Medical Center, Boston, Massachusetts

Rosy Suleman, PharmD Regional Scientific Associate Director Novartis Pharmaceuticals Corporation Carlsbad, California

US Pharm. 2007;32(5):HS-5-HS-19.

Millions of people in the United States undergo surgery or are injured each year.1 Yet, for people from all different backgrounds and in various stages of life, as well as those with underlying medical conditions, the treatment of pain is less than ideal.2-10 This issue reflects deeply seated issues pertaining to all levels of the health care system and society. Furthermore, undertreated pain has important clinical, economic, and human outcomes. Effects include increased catabolic demand, decreased movement, cough suppression, and shallow breathing; increased use of medical resources; and reduced health-related quality of life (including diminished physical functioning).11-17 Evidence indicates that cellular and molecular changes seen in chronic pain begin to appear with the initial injury, supporting the observation that undertreated acute pain is a risk factor for chronic pain and that acute and chronic pain exist on a continuum.18

The systematic undertreatment of pain represents a public health crisis in this country. While all health care professionals must have knowledge of the tools used to help treat pain, pharmacists have a particularly significant role because they are highly visible and accessible members of the health care team. The purpose of this article is to review clinical issues related to the pharmacotherapy of acute pain that community-based pharmacists are likely to encounter. Before the pharmacotherapy of acute pain is discussed, it is important to ensure the use of a common language to help avoid the impassioned and often mistaken use of vocabulary that contributes to existing pain management obstacles.

Defining Pain According to the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.19 Pain may be described in terms of this damage. The definition of pain is often subjective, being whatever the person says it is, existing whenever the person says it does.20

From these definitions, it is clear that pain is a complex, multidimensional, subjective experience, and that the relationship between tissue damage and pain intensity is variable. Additionally, the inability to communicate the presence of pain does not in any way suggest that pain is absent. Because pain is subjective, health care providers must rely on the person's report, even when reported pain and behavior do not seem to match.

While pain is often described using terms like acute and chronic, these and other distinctions can be misleading. For example, acute pain is often described as a recent onset that tends to diminish with time, while chronic pain tends to last longer than is expected for the injury to heal.21 Acute pain can be long-lasting; people often do not conform to expectations; and mixed types of pain can be present at the same time. For example, patients with cancer may experience pain that is acute, chronic, or some hybrid of these concepts. Other examples include a person with chronic arthritis pain who undergoes surgery, a person with cancer-related pain who also experiences episodes of breakthrough pain, or a person with low back pain who is injured in a car accident. In each setting, the affected patient will experience pain with mixed features.

Pain is commonly referred to in terms that reflect the underlying location or pathophysiology, such as nociceptive or neuropathic.19,20 Nociceptive pain results from pressure, temperature, or chemical stimuli. This type of pain is also classified as originating from skin, bones, muscle, and connective tissue (somatic) or internal organs (visceral).20 In general, somatic pain tends to be specifically located, while visceral pain is more diffuse. In contrast to nociceptive origins, nerve or nervous system damage may result in neuropathic pain.19 This type of pain may be central, as with some poststroke syndromes, or peripheral, such as diabetic neuropathy or postherpetic neuralgia.

Dependence, Tolerance, and Addiction Much of the confusion about pain management involves these concepts. Yet, rather than allowing this confusion to interfere with the ability and willingness of clinicians to provide effective pain management, pharmacists and their colleagues on the health care team, patients, and families must be educated about these phenomena.

If a patient taking a drug develops a withdrawal syndrome when that substance is suddenly removed, the individual is physically dependent on that substance.22 For opioid analgesics, the withdrawal syndrome generally includes signs of central arousal, such as insomnia, irritability, and agitation. Patients may also experience autonomic symptoms, including diarrhea, rhinorrhea, and sweating, as well as muscle spasms, gastrointestinal cramping, and other painful phenomena.

It is critically important to understand that dependence is an expected physiologic response to use of certain drugs and neither a sufficient nor a necessary aspect of addiction. 22-24 Although we often think of dependence relative to use of opioid analgesics, this concept also applies to any other drug (or pharmacologic class) for which suddenly stopping use is discouraged. Typically, the best way to avoid development of a withdrawal syndrome in a person thought to be dependent on a drug is to slowly decrease the dose.

Similarly, tolerance refers to the need for increased doses to produce a particular effect.22 For a given drug, however, a person may become tolerant to some effects but not to others. For example, with the opioid analgesics, tolerance to sedation and respiratory effects typically develops quickly, while people generally develop tolerance to the constipating effects of these drugs slowly, if at all. For this reason, a preventive bowel regimen is considered a routine part of therapy for individuals expected to be on opioid analgesics for an extended period of time.

Addiction is probably one of the most misunderstood phenomena associated with the use of opioid analgesics. As defined by the American Pain Society, American Society of Addiction Medicine, and American Academy of Pain Medicine, this primary, chronic, neurobiological disease has genetic, psychosocial, and environmental dimensions.22-24 Addicted individuals may have impaired control over their drug use, compulsive use of the substance, continued use despite harm, and craving for the substance. Furthermore, evidence in biomedical literature overwhelmingly indicates that the rate of iatrogenic addiction among persons who are being treated for acute pain, and who do not have a history of substance abuse, is vanishingly low.25-29 This evidence and our understanding of addiction support the contention that people who use opioid analgesics to relieve their pain on a mutually agreed-upon schedule without aberrant behaviors, whose functioning and pain control are relatively stable, and who are willing to consider various treatment options are unlikely to become addicted.22-24 As a result, concern about causing a patient to become addicted should not contribute to clinical decisions about how to treat pain, nor to patients' willingness to use appropriately prescribed analgesics.23,25-29

While evidence indicates that the risk of iatrogenic addiction in persons who are treated for acute pain is nearly zero, systematic undertreatment of pain--including use of subpotent analgesics, dosing regimens that do not reflect the pharmacokinetics and pharmacodynamics of the analgesic, and inappropriate reliance on as-needed use of these drugs--is common. Moreover, not only does the systematic undertreatment of pain unfairly penalize persons with pain, it can also directly result in a phenomenon known as pseudoaddiction.30 In this syndrome, the patient may (unsurprisingly) request analgesics before the next scheduled dose, doctor-shop, and act in other ways that are seen in persons who abuse substances. The distinction is that when an undertreated individual's pain is appropriately treated, these aberrant behaviors disappear. Rather than waiting for a problem to develop, however, pseudoaddiction can be avoided by building trust between the patient and the health care team, using analgesics on a regular schedule instead of an as-needed basis, and using adjuvants and nondrug treatments.

Evidence of Undertreated Pain During the past four decades, there have been numerous published reports of suboptimally treated pain among persons with acute pain.2-10 Progress in improving the care for these individuals has continued, but it has been done slowly and fitfully and has been less successful than might be expected, given the availability of potent analgesics and clinical practice guidelines to help clinicians.3,31-33 Well-documented barriers to effective evidence-based pain management include deficiencies in pre- and postgraduate health professions education; incorrectly held attitudes and beliefs about opioid analgesics, adverse effects, and pain itself; and fear of prosecution. 3,34-41

Pain Pharmacotherapy Nonopioids: These drugs include salicylates, acetaminophen, and the NSAIDs. They are at least generally familiar to almost everyone, since they are nearly ubiquitous in prescription and OTC medications. These drugs are used primarily for mild to moderate pain, although in combination with opioids, they are often used for more intense pain.

Acetaminophen is a centrally acting analgesic that does not have significant anti-inflammatory activity, nor does it affect platelets or gastric mucosa.42 Despite a generally favorable toxicity profile, acetaminophen must be used cautiously because it is potentially hepatotoxic, particularly in persons with hepatic or renal disease, chronic alcoholism, or malnutrition. Even in otherwise healthy adults, the maximum daily dose of acetaminophen from all sources should not exceed 4,000 mg.42,43 This is important because acetaminophen is used in fixed-combination drugs with opioid analgesics. While there is no set ceiling dose for opioids, there is a clearly identified limit for acetaminophen, which can result in an unnecessary, artificial barrier to optimal analgesia.

Additionally, the rectal absorption of acetaminophen is variable, and this can affect the doses needed to provide pain relief. For example, although the recommended pediatric oral dose of acetaminophen is 10 to 15 mg/kg every six hours, a rectal loading dose of 40 mg/kg with maintenance doses of 20 mg/kg every six hours has been found to be safe and effective in at least one study.44,45

NSAIDs are also commonly used for a wide variety of painful conditions and have proven effective in treating postoperative pain. As their name suggests, these agents inhibit central and peripheral prostaglandin synthesis, diminishing inflammation. Yet, because NSAIDs do not affect circulating pros taglandins, pain relief occurs sooner than anti-inflammatory effects.18 As with acetaminophen, the NSAIDs have a ceiling effect, beyond which therapeutic benefit does not increase, but the risk of adverse effects, including nausea, vomiting, and gastrointestinal bleeding, does increase. This observation is particularly important, since NSAID use results in significant morbidity and mortality in the U.S. Despite these well-described risks, the risk-benefit ratio of NSAIDs remains generally favorable in terms of their therapeutic potential.

Cyclooxygenase-2 (COX-2) Inhibitors: Many questions remain about the possible role of COX-2 selective inhibitors in clinical practice. While these drugs are similarly efficacious to nonselective NSAIDS, the main argument for use of COX-2 inhibitors has always been safety, and it is here that many unresolved issues persist. For example, rofecoxib and valdecoxib were withdrawn from the U.S. market for safety concerns. In addition, in a large, randomized trial, individuals with rheumatoid arthritis or osteoarthritis who took celecoxib had fewer symptomatic upper GI ulcers and related complications than individuals who took ibuprofen or diclofenac over the first six months of use, although this benefit disappeared by the end of one year of use.46,47 There is also some evidence suggesting that a clinically important drug interaction may occur between warfarin and COX-2 inhibitors.48,49 Other compounds in this class are in various stages of clinical development; thus, it remains to be seen whether the benefit in persons with arthritis occurs immediately and if this effect is broadly generalizable.

Opioids: Without a doubt, opioids have an important and useful role in the treatment of moderate to severe pain. Notably, these drugs should not be referred to as narcotics, a term that has been associated with barriers to optimal pain management and that fails to clearly identify the specific type of drug.23

Opioids are often classified by their activity at mu, kappa, or delta receptors in the central nervous system.50,51 Effects of the mu- and kappa-receptor agonists include analgesia. Mu-agonists also affect mood and reward behavior, and while kappa-active drugs may produce less respiratory depression and miosis, these drugs are also associated with dysphoria. It is important to remember that in the dosage range typically used to treat acute pain, the mu-receptor agonists have no therapeutic dosage ceiling.50,51 Provided that the person is getting pain relief and is not having intolerable side effects, the dose of the opioid analgesic can be increased. Opioid analgesics also lack the adverse effects associated with NSAIDs, and people who do not respond to one opioid may still respond to another.

Currently available opioid analgesics and antagonists are listed in Table 1. Most of the opioid analgesics are mu-receptor agonists, although several are mu-receptor antagonists and kappa-receptor agonists. The mixed-activity drugs (once commonly called mixed agonist-antagonists) were designed to provide a lower risk of respiratory depression and abuse but when used in equianalgesic doses, their rate of adverse effects is comparable to that of the mu-receptor agonists.50,51 Furthermore, there is a consistent dose-response relationship with the mu-receptor agonists, but the kappa-receptor agonist/mu-receptor antagonist drugs are not thought to possess that quality.

Opioids to Avoid: The role for codeine, meperidine, and propoxyphene in acute pain management is limited, regardless of the route of administration. Codeine is a prodrug and must be converted to morphine via the cytochrome P-4502D6 pathway.53 About 10% of a codeine dose is converted to morphine, which is about 30% bioavailable. As a result, 30 mg of codeine provides just 1 mg of morphine. Persons who lack the ability to metabolize codeine to morphine get no analgesia from the drug, although they are still at risk for dose-limiting adverse effects, which commonly occur.51

Meperidine is about 1/10 as potent as morphine on a milligram-to-milligram basis; thus, a 75-mg dose of meperidine is equivalent to about 5 to 7.5 mg of morphine.3 A dosing interval of four to six hours is often used for meperidine, but the drug provides analgesia for 2.5 to three hours. As a result, 100 to 150 mg of meperidine every three hours would be needed to provide analgesia equivalent to 10 mg of morphine every four hours.3

Meperidine's active metabolite normeperidine is renally eliminated. Normeperidine is neurotoxic and can cause a variety of serious adverse effects, including seizures, even in persons with normal renal function.23,53,54 Additionally, concomitant therapy with meperidine and monoamine oxidase inhibitors (MAOI) (or use within two weeks of discontinuation of the MAOI), including seligilene, is absolutely contraindicated due to a risk of hypertensive crisis, hyperpyrexia, and cardiovascular system collapse.55 Use of meperidine should be avoided whenever possible. If use of this analgesic is unavoidable, American Pain Society guidelines recommend use for no more than 48 hours and at doses no more than 600 mg per 24 hours in persons with normal renal function.3

Propoxyphene has no clinical advantages over acetaminophen.3,56 Like meperidine, propoxyphene also has an active, toxic metabolite norpropoxyphene that accumulates in persons with decreased renal function.53,57 This metabolite is also associated with an increased incidence of falls in elderly individuals.58

Equianalgesic Conversion: Morphine is the prototypical opioid analgesic. However, there are times when it is desirable to use one of the other drugs in this class. For example, an individual may be allergic or hypersensitive, intolerable adverse effects may occur, or the drug may not provide the desired degree of pain relief. Pharmacokinetic considerations may also have an impact. For example, neither hydromorphone nor oxycodone have clinically active metabolites, so these agents are often preferred in people with diminished renal function.

At equianalgesic doses, the opioid analgesics have similar efficacy, although adverse-effect profiles may vary. There are a variety of dose-conversion tables and methods available, and different results are common depending on the method used. Some evidence also suggests that conversion factors differ based on the drug used, the drug that it is being converted to, and whether the person is opioid-naïve or opioid-tolerant.21,59,60

A good example of this phenomenon is methadone. While methadone was once used mainly for opioid maintenance programs, its use as an analgesic has increased substantially over the past few years. As a result, pharmacists in community practice are much more likely to encounter its use. Methadone is generally considered to be equipotent to morphine in opioid-naïve individuals, but its elimination half-life is much longer than its biologic half-life, and it is also an N -methyl-d-aspartate (NMDA) receptor antagonist. As a result, large decreases in methadone doses (~90%) may be needed over the first few days after changing analgesics. Failing to account for this phenomenon can contribute to serious and even fatal adverse events.

Several methods for calculating equianalgesic doses are used; some use tables in pharmacy references commonly available, while others take relative potency and pharmacokinetic parameters into account.21,59,60 Two of these methods are shown in Table 2; however, it is important to recognize that major differences between methods can result. For example, converting from morphine to oxycodone using method 1 in the table indicates that 48 mg of intravenous morphine is equivalent to 96 mg of oral oxycodone, while using method 2 provides a result of 60 mg of oral oxycodone. One difference between these approaches is that in the first method, 20 mg of oral oxycodone is considered to be equivalent to 30 mg of oral morphine. This conversion factor is frequently used, but for this to be true, oxycodone would have to be about 50% bioavailable, rather than 80%.21 Method 2, in contrast, accounts for potency and bioavailability of these drugs.

To help avoid cases of serious overdose, one approach is to decrease the dose of the new opioid by approximately 25% to 50% to account for incomplete cross-tolerance. However, the percentage decrease depends on how well the person's pain is being controlled, among other factors.61

Role of Community Pharmacists There is ample evidence documenting pharmacists' impact in helping reduce adverse drug events and their associated costs in hospitalized persons.61-63 Thus, it is logical to question how to best assess the contribution that community-based pharmacists can make to patient outcomes. An example of this effort was described in a study on the feasibility of health outcomes assessment in community pharmacy practices.64 Individuals who participated in this project had been diagnosed with osteoarthritis, rheumatoid arthritis, or low back pain, among other musculoskeletal disorders. Study participants met with a pharmacist every three months for a year and completed a survey that included condition-specific items and the SF-36, as well as questions about the use of medical resources. The SF-36 is used to estimate the effects of illness or medical conditions on health-related dimensions of quality of life that are believed to be universally important and are not age, treatment, or disease specific.65 Data collected in this study help indicate how these conditions affect health-related quality of life. There is no way to understand the effects of health care on individuals unless health care providers ask. This information can help identify people who experience adverse effects from their medications or who need additional attention in order to improve their therapeutic regimen. Possibly more important, these data show that it is possible to collect this information in community pharmacies. Given the numerous demands on pharmacists' time and attention, it is encouraging to see the potential of community pharmacists to contribute to patient care.

There are a wide variety of ways that pharmacists can help care for persons with pain. Their roles include compounding and dispensing; serving as a resource for clinicians, patients, and family members; advocating on behalf of patients suffering from pain; and helping ensure continuity of care.66 As the number of people who undergo outpatient surgical procedures rises and pressure increases to discharge hospitalized individuals as soon as they are medically stable, this latter point will become increasingly important.

Conclusion The promise of relief from pain exerts a powerful attraction, leading people in distress to seek medical care. Pain is a universal part of being human, and yet, evidence demonstrates that people from all backgrounds, stages of life, and levels of health experience less than optimal treatment of their pain. This situation exists for many reasons that pertain to our health care system and society.

Improving pain management is complex and multidimensional--much like pain itself--and there are many important challenges clinicians must face. Yet, there is good news: Because of pharmacists' visibility and ready accessibility, there are ample opportunities for us to become leaders in this effort.

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Ann Intern Med. 2007 May 15;146(10):726-34.

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Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia.

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We present here an example case of neuropathic pain with heat allodynia as a major symptom to illustrate how the functional imaging of pain may provide new insights into the pathophysiology of painful sensory disorders. Tissue injury of almost any kind, but especially peripheral or central neural tissue injury, can lead to long-lasting spinal and supraspinal re-organization that includes the forebrain. These forebrain changes may be adaptive and facilitate functional recovery, or they may be maladaptive, preventing or prolonging the painful condition, and interfering with treatment. In an experimental model of heat allodynia, we used functional brain imaging to show that: (1) the forebrain activity during heat allodynia is different from that during normal heat pain, and (2) during heat allodynia, specific cortical areas, specifically the dorsolateral prefrontal cortex, can attenuate specific components of the pain experience, such as affect, by reducing the functional connectivity of subcortical pathways. The forebrain of patients with chronic neuropathic pain may undergo pathologically induced changes that can impair the clinical response to all forms of treatment. Functional imaging, including PET, fMRI, and neurophysiological techniques, should help identify brain mechanisms that are critical targets for more effective and more specific treatments for chronic, neuropathic pain.

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