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Chronic Pain Clinical Trials, Diagnosis, and Treatment
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Chronic Pain

Chronic pain is defined as pain that persists longer than the temporal course of natural healing, associated with a particular type of injury or disease process.

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." It is important to note that pain is subjective in nature and is defined by the person experiencing it, and the medical community's understanding of chronic pain now includes the impact that the mind has in processing and interpreting pain signals.

Current Research

For current research articles click - here

Functional Anatomy

The anatomy of the nociceptive system can be grossly divided into the peripheral and central nervous system. The peripheral nervous system consists of small myelinated and unmyelinated nerve fibers. These nerve fibers converge into a region of the spinal cord referred to as the dorsal horn. The dorsal horn is the first relay station in pain signal transmission. The next element of pain transmission includes nerve fibers that then travel to the thalamus. From the thalamus the next order of neurons ascend to the limbic system and sensory cortex. This accounts for the affective elements and discriminative of pain respectively.

Nociception

Nociceptors convey information regarding damage or trauma from the body to the central nervous system, a process called nociception, where it is interpreted by the brain as pain. Nociception occurs in any tissue or organ in which pain signals arise secondary to a disease process or trauma. The nociception can also occur if there is dysfunction or damage to nerves themselves.

Pathophysiology

Under persistent activation nociceptive transmission to the dorsal horn may induce a wind up phenomenon. This induces pathological changes that lower the threshold for pain signals to be transmitted. In addition it may generate nonnociceptive nerve fibers to respond to pain signals. Nonnociceptive nerve fibers may also be able to generate and transmit pain signals. In chronic pain this process is difficult to reverse or eradicate once established.

Classification

Nociception (pain) may arise from injury or disease to visceral, somatic and neural structures in the body. More broadly pain is described as malignant or non-malignant in origin.

Diagnoses

Pain may be a response to injury or any number of disease states that provoke nociception. Advances in imaging studies and electrophysiological studies allow us to gain a deeper insight into the characteristics and properties associated with the phenomenon of chronic pain.

Related Sequelae

Chronic pain may cause other symptoms or conditions, including depression and anxiety. It may also contribute to decreased physical activity given the apprehension of exacerbating pain. Conversely it may itself have psychosomatic or psychogenic component to its cause. Very little work has been done on the cognitive effects of chronic pain, with most of the publications focussing on the effects of cognition on pain but only 5% examining the effects of pain on cognition.

Attention

Chronic pain impairs the ability to direct attention, in particular when compared to peers with low intensity or no chronic pain, people with high-intensity chronic pain have significantly reduced ability to perform attention-demanding tasks. The pain sensations appear to strongly capture the attention of people with chronic pain; tests assessing the ability to attend show poorer performance than peers who do not experience chronic pain on all tests demanding attention. The exception is found with tasks that are highly demanding of attention, where performance between the two groups is equivalent. In experimental testing, two-thirds of individuals with chronic pain demonstrate clinically significant impairment of attention, independent of age, education, medication and sleep disruption. Individuals with the highest levels of pain showed greatest disruption of memory traces, suggesting that pain diminishes working memory.

Management

It is rare to completely achieve absolute and sustained relief of pain. Thus, the clinical goal is pain management. Pain management is often multidisciplinary in nature. A recent journal article by Gatchell and Okifuji recognizes the importance of comprehensive pain programs(CPPs) in the management of chronic pain. They summarize their findings as follows: "CPPs offer the most efficacious and cost-effective treatment for persons with chronic pain, relative to a host of widely used conventional medical treatment."

Medications

In the treatment of chronic pain, whether due to malignant or benign processes, the three-step WHO Analgesic Ladder is often used. This provides guidelines for stepping up the amount of analgesia and maintains a general basis that is used in a number of countries around the world to manage chronic pain conditions. The exact medications recommended will vary with the country and the individual treatment centre, but the following gives an example of the approach to treating chronic pain with medications. If, at any point, treatment fails to provide adequate pain relief, then the doctor and patient move onto the next step.

Mild Pain

Paracetamol (acetaminophen), or a non steroidal anti-inflammatory drug such as ibuprofen

Mild to Moderate Pain

Paracetamol, an NSAID and/or paracetamol in a combination product with a weak opioid such as hydrocodone; used in combination, may provide greater relief than their separate use.

Moderate to Severe Pain

Morphine is the gold standard choice, followed by Oxycodone, Fentanyl in the form of a transdermal patch designed for chronic pain management, Diamorphine, hydromorphone or methadone are used less frequently.

Pethidine is not recommended for chronic pain management due to its low potency, short duration of action, and toxicity associated with repeated use.

Opioids

Opioid medications can provide a short, intermediate or long acting analgesia depending upon the specific properties of the medication and whether it is formulated as an extended release drug. Opioid medications may be administered orally, by injection, via nasal mucosa or oral mucosa, rectal, transdermal, intravenously, epidurally and intrathecally. In chronic pain conditions that are opioid responsive a combination of a long acting or extended release medication is often prescribed in conjunction with a shorter acting medication for break through pain (exacerbations).

Most opioid treatment is oral (tablet, capsule or liquid), but suppositories and skin patches can be prescribed. An opioid injection is rarely needed for patients with chronic pain.

Although opioids are strong analgesics, they do not provide complete analgesia regardless of whether the pain is acute or chronic in origin. Opioids are efficacious analgesics in chronic malignant pain and modestly effective nonmalignant pain management. However, there are variable associated adverse effects, especially during the commencement or change in dosing and administration. When opioids are used for prolonged periods drug tolerance, chemical dependency and (rarely) addiction may occur. Chemical dependency is ubiquitous among opioid therapy after continuous administration; however, drug tolerance is not well studied in patients on long term opioid therapy. Addiction rarely occurs as a result of opioid prescription, but they are abused by some individuals, which can cause concern to health care providers. Diversion of opioid medications is another concern for health care providers.

Non-Steroidal Anti-Inflammatory Drugs

The other major group of analgesics are Non-steroidal anti-inflammatory drugs (NSAID). This class of medications does not include acetaminophen, which has minimal anti-inflammatory properties. However, acetaminophen may be administered as a single medication or in combination with other analgesics (both NSAIDs and opioids). The alternatively prescribed NSAIDs such as ketoprofen and piroxicam, have limited benefit in chronic pain disorders and with long term use is associated with significant adverse effects. The use of selective NSAIDs designated as selective COX-2 inhibitors have significant cardiovascular and cerebrovascular risks which have limited their utilization.

Antidepressants and Antiepileptic Drugs

Some antidepressant and antiepileptic drugs are used in chronic pain management and act primarily within the pain pathways of the central nervous system, though peripheral mechanisms have been attributed as well. These mechanisms vary and in general are more effective in neuropathic pain disorders as well as complex regional pain syndrome. Drugs such as Gabapentin have been widely prescribed for the off-label use of pain control. The list of side effects for these classes of drugs are typically much longer than opiate or NSAID treatments for chronic pain, and many antiepileptics cannot be suddenly stopped without the risk of seizure.

Other Adjuvant & Atypical Analgesic Agents

Other drugs are often used to help analgesics combat various types of pain and parts of the overall pain experience. In addition to gabapentin, the vast majority of which is used off-label for this purpose, orphenadrine, cyclobenzaprine, trazadone and other drugs with anticholinergic properties are useful in conjunction with opioids for neuropathic pain. The latter three drugs are also muscle relaxants and are therefore particularly useful in painful musculoskeletal conditions. Clonidine has found use as an analgesic for this same purpose and all of the mentioned drugs potentiate the effects of opioids overall.

Interventional Therapy

Pulsed radiofrequency, neuromodulation, direct introduction of medication and nerve ablation may be used to target either the tissue structures and organ/systems responsible for persistent nociception or the nociceptors from the structures implicated as the source of chronic pain.

An intrathecal pump used to delivery very small quantities of medications directly to the spinal fluid. This is similar to epidural infusions used in labour and postoperatively. The major differences are that it is much more common for the drug to be delivered into the spinal fluid (intrathecal) rather than epidurally, and the pump can be fully implanted under the skin. This approach allows the drug to be delivered directly to the site of action, ie the spinal cord, and so allows a higher dose to be given with less systemic side effects.

A spinal cord stimulator is an implantable medical device that creates electric impulses and applies them near the dorsal surface of the spinal cord provides a paresthesia ("tingling") sensation that alters the perception of pain by the patient.

Rehabilitation

As alluded to earlier there are other modalities used in the treatment of chronic pain. These include: physical modalities such as thermal agents and electrotherapy. Complementary and alternative medicine, therapeutic exercise and behavioral therapy are also utilized autonomously or in tandem with interventional techniques and conventional pharmacotherapy. This is most often structured in a multidisciplinary or interdisciplinary program.

Behavioral Therapy

Applied behavior analysis treats pain as mixture of respondent and operant conditioning in which normal tissues learn to fire pain responses in the presence of specific environmental antecedents and consequences. The model was first proposed by Fordyce in 1976. There is mixed support for behavioral treatment of pain, with many studies reporting positive results, though a review of studies in 2005 suggested that though behavioral can be an effective and economical means of treating chronic pain, a substantial portion of patients do not benefit from behavior therapy, that effects are rather modest, and there is little evidence to support different treatment modalities have different effects.

Biofeedback

Biofeedback based on behavioral principles has shown some success for chronic pain, demonstrating greater improvement in one study than peers undergoing cognitive-behavioral therapy and conservative medical treatment, though a different study showed improvements over wait-list controls but no difference between biofeedback and cognitive-behavioral therapy.


(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Chronic_pain)





Findings From Current Research

Barriers to Pain Assessment and Management in Cancer Survivorship

Authors: Sun V, Borneman T, Piper B, Koczywas M, Ferrell B.

Department of Nursing Research and Education, Division of Population Sciences, City of Hope, Duarte, CA 91010, USA. vsun@coh.org

INTRODUCTION: Healthcare providers frequently lack the knowledge and skills to provide optimal pain management for cancer survivors. Scientific evidence and clinical guidelines are lacking in the management of chronic, persistent pain in survivors. The purpose of this article is to describe pain-related issues of cancer survivors using case presentations of selected patients enrolled in a randomized trial to eliminate barriers to pain management. MATERIALS AND METHODS: Case presentations were selected from a National Cancer Institute-funded study that utilizes patient and professional educational content derived from the clinical guidelines of the National Comprehensive Cancer Network. Case presentation criteria included a pain rating of >or=6 and diagnosis of Stage I, II, or III of the following cancers: breast, colon, lung, or prostate cancer. Cases are presented based on the study's framework of patient, professional, and system-related barriers to optimal pain relief. RESULTS: Across all three case presentations, barriers such as fear of side effects from pain medications, fear of addiction, lack of professional knowledge of the basic principles of pain management, and lack of timely access to pain medications due to reimbursement issues are prevalent in cancer survivorship. CONCLUSIONS: Chronic pain syndromes related to cancer treatments are common in cancer survivors. Patient, professional, and system-related barriers that are seen during active treatment continue to hinder optimal pain relief during survivorship. IMPLICATIONS FOR CANCER SURVIVORS: Healthcare providers must acknowledge the impact of chronic, persistent pain on the quality of cancer survivorship. Clinical as well as scientific efforts to increase knowledge in chronic pain management will improve the symptom management of cancer survivors.

Journal: J Cancer Surviv. 2008 Mar;2(1):65-71. Epub 2008 Feb 15.
Adapted from PubMed; click here to access full journal article.




Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Pain

Authors: Nnoaham KE, Kumbang J.

Public Health Medicine, University of Oxford, Rosemary Rue Building, Old Road Campus, Headington, Oxford, Oxfordshire, UK, OX3 7LF.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a popular pain treatment modality but its effectiveness in chronic pain management is unknown. This review is an update of the original Cochrane review published in Issue 3, 2001. OBJECTIVES: To evaluate the effectiveness of TENS in chronic pain. SEARCH STRATEGY: The Cochrane Library, EMBASE, MEDLINE and CINAHL were searched. Reference lists from retrieved reports and reviews were examined. Date of the most recent search: April 2008. SELECTION CRITERIA: RCTs were eligible if they compared active TENS versus sham TENS controls; active TENS versus 'no treatment' controls; or active TENS versus active TENS controls (e.g. High Frequency TENS (HFTENS) versus Low Frequency TENS (LFTENS)). Studies of chronic pain for three months or more which included subjective outcome measures for pain intensity or relief were eligible for evaluation. No restrictions were made to language or sample size. Abstracts, letters, or unpublished studies, and studies of TENS in angina, headache, migraine, dysmenorrhoea and cancer-related pain were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted and summarised on the following items: patients and details of pain condition, treatments, study duration, design, methods, subjective pain outcome measures, methodological quality, results for pain outcome measures and adverse effects, and conclusions by authors of the studies. Extracted data and methodological quality of studies were confirmed by the review authors. MAIN RESULTS: Of 124 studies identified from the searches, 99 did not fulfil pre-defined entry criteria. Twenty-five RCTs involving 1281 participants were evaluated. Included studies varied in design, analgesic outcomes, chronic pain conditions, TENS treatments and methodological quality. The reporting of methods and results for analgesic outcomes were inconsistent across studies and generally poor. Meta-analysis was not possible. Overall in 13 of 22 inactive control studies, there was a positive analgesic outcome in favour of active TENS treatments. For multiple dose treatment comparison studies, eight of fifteen were considered to be in favour of the active TENS treatments. Seven of the nine active controlled studies found no difference in analgesic efficacy between High Frequency (HF) TENS and Low Frequency (LF) TENS. AUTHORS' CONCLUSIONS: Since the last version of this review, new relevant studies have not provided additional information to change the conclusions. Published literature on the subject lacks the methodological rigour or robust reporting needed to make confident assessments of the role of TENS in chronic pain management. Large multi-centre RCTs of TENS in chronic pain are still needed.

Journal: Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003222.
Adapted from PubMed; click here to access full journal article.




The Impact of Pain on Quality of Life and the Unmet Needs of Pain Management: Results from Pain Sufferers and Physicians Participating in an Internet Survey

Authors: McCarberg BH, Nicholson BD, Todd KH, Palmer T, Penles L.

University of California, San Diego, CA, USA. Bill.H.McCarberg@kp.org

Pain is one of the most common medical complaints, but despite its prevalence, many individuals still suffer with unrelieved or undertreated pain. This marketing research survey was designed to determine the physical, psychological, and economic impact pain has on the lives of individuals suffering with pain and to identify the unmet needs of patients who have taken opioid medications to treat their pain. In addition, the survey sought to address the challenges physicians face when treating patients with pain. Pain sufferers were recruited through e-mail invitation to an Internet survey; 173,854 invitations were sent out, 22,018 people responded (12.7%), and 606 met the criteria for inclusion in the survey as pain sufferers. Of these, 359 people had moderate to moderately severe chronic pain and 247 people had moderate to moderately severe acute pain. Additionally, physicians currently treating pain were recruited through e-mail and postal mail invitations and 492 met eligibility criteria: 241 specialists (orthopedic or general surgeons, pain specialists or anesthesiologists), 125 primary care, and 126 emergency medicine physicians. Results of this survey supported what many physicians observe in their practice and hear from their patients, that pain has a negative impact on daily activities in the majority of pain sufferers. Many chronic pain sufferers reported that pain had deleterious effects on their mental health, employment status, sleep, and personal relationships. The impact of pain on patient quality of life and the unmet needs in pain management were recognized by the majority of physicians surveyed, with inadequate pain control, end-of-dose pain, and side effects associated with increased dosing reported as negative factors influencing their choice of pain medication. In conclusion, effective communication between physicians and patients is encouraged to not only improve overall pain management but also to establish shared treatment goals with functional outcomes.

Journal: Am J Ther. 2008 Jul-Aug;15(4):312-20.
Adapted from PubMed; click here to access full journal article.




Pharmacotherapeutic Management of Breakthrough Pain in Patients with Chronic Persistent Pain

Authors: Fishbain DA.

Miller School of Medicine at the University of Miami, 304A Dominion Tower, 1400 NW 10th Ave, Miami, FL 33136, USA. dfishbain@med.miami.edu

Breakthrough pain (BTP) is experienced by many patients being treated with opioids for the management of chronic persistent pain. Control of BTP has been problematic since, until recently, the pharmacokinetics of older treatments was largely incompatible with the onset and duration of these pain episodes. Newer agents are now available that better approximate the timing of BTP episodes, and their use is increasingly being integrated into opioid-based pain management strategies. Successful management of BTP can improve treatment satisfaction and the quality of life of patients with chronic persistent pain of both cancer and noncancer origins. This article reviews the types of BTP, the therapeutic options available to manage BTP, and the tools designed to detect and minimize the risk of aberrant drug-related behaviors potentially associated with opioid medications.

Journal: Am J Manag Care. 2008 May;14(5 Suppl 1):S123-8.
Adapted from PubMed; click here to access full journal article.




Breakthrough Pain in the Management of Chronic Persistent Pain Syndromes

Authors: Webster LR.

Lifetree Clinical Research and Pain Clinic, 3838 S 700 E, Ste 200, Salt Lake City, UT 84106, USA. lynnw@lifetreepain.com

Chronic pain results from tissue damage (nociceptive) or damage to the nerves or nervous system (neuropathic); it can stem from internal organs or cavity linings (visceral) or from the body's tissues (somatic). Mixed pain results from any number or combination of these types. Breakthrough pain (BTP) is a transitory, and often excruciating, flare that occurs against a background of chronic pain otherwise controlled by opioids. BTP is highly prevalent in patients with chronic pain of both cancer and noncancer origin, with episodes typically occurring several times daily that tend to peak within 10 to 30 minutes. Patients with BTP also endure heightened chronic pain, worsened physical function, and psychological distress. Several subtypes of BTP have been identified, including idiopathic, incident, and end-of-dose failure. The BTP Questionnaire is available to identify and characterize BTP and help determine the best treatment strategy for individual patients. This article reviews the etiology, prevalence, and characteristics of BTP along with assessment of patients and therapeutic strategies available to treat this condition.

Journal: Am J Manag Care. 2008 May;14(5 Suppl 1):S116-22.
Adapted from PubMed; click here to access full journal article.




Interpreting Urine Drug Tests: Prevalence of Morphine Metabolism to Hydromorphone in Chronic Pain Patients Treated with Morphine

Authors: Wasan AD, Michna E, Janfaza D, Greenfield S, Teter CJ, Jamison RN.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective. : Pain medicine practitioners frequently use urine drug testing (UDT) to monitor adherence to opioid therapy. It can be difficult to interpret a result as normal or abnormal in relation to which opioid compounds are expected to be found in the urine. We investigated whether hydromorphone may be a metabolite of morphine normally appearing in UDT of patients prescribed morphine. Design. : This is a retrospective case-control study of urine toxicology results in pain patients taking only morphine. Inclusion criteria included urine results positive for morphine only (controls) or morphine and hydromorphone (cases). Demographic and medical history variables, and any history of aberrant drug behavior were recorded and related to the presence or absence of hydromorphone in the urine. Results. : Hydromorphone was present in 21 of 32 cases (66%), none of whom had a history of aberrant drug behavior. Positive cases occurred more frequently in women, in those taking higher daily doses of morphine, and in those with higher urine morphine concentrations (P < 0.05). Only morphine urine concentration was a significant predictor of the hydromorphone metabolite in a logistic regression model (P < 0.05). Conclusions. : Hydromorphone is likely a minor metabolite of morphine, normally appearing in the UDT of patients taking morphine. This finding assists in determining whether a UDT result is normal or abnormal, and subsequently whether a patient is compliant with opioid therapy. This observation should be confirmed by a prospective study in a controlled environment. Variables such as gender, morphine dose, morphine urine concentration, and genetic determinants of morphine metabolism should be investigated further.

Journal: Pain Med. 2007 Aug 28.
Adapted from PubMed; click here to access full journal article.





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