Contents part 1: Introduction




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Programs that allow some opioid use


Mayo Clinic Pain Rehabilitation Program: This program also incorporates simultaneous opioid withdrawal and pain rehabilitation. The original study by Rome et al. was designed to (1) evaluate the frequency of maintenance opioid therapy in the population admitted to the multidisciplinary program, (2) compare demographic characteristics, pain severity, emotional distress, and level of function of patients taking maintenance opioids at admission vs. those who were not, (3) compare outcomes of the two groups (pain severity, interference with pain, perceived life control, affective distress, general activity level, depression, and catastrophizing). Research (in an analysis of predominately female, non-workers’ compensation patients), found that all patients that completed the program (regardless of opioid use on initial entry) showed decreased pain severity and catastrophizing, although those taking opioids had significantly higher scores at the three-week discharge for these variables. They also had higher scores for depression. Over one-half of patients took opioids at the time of admission (57.1%). The majority of patients completed the program (91%). At the completion of treatment 13.9% of patients were still taking opioids (mean oral morphine equivalents a day of 67.6 mg/day). Significant improvement was found for all outcome variables immediately after completion of the program and at 6-months post-treatment regardless of opioid status at admission. In this program, there was no difference between opioid and non-opioid groups upon discharge or at six-months of follow-up, post-treatment. The conclusion of the researchers was that opioid withdrawal did not prohibit rehabilitation gains. (Rome, 2004)

Specific Evaluation Studies: A specific assessment of the use of opioids on treatment outcomes was undertaken by Townsend et al. (Townsend 2008) On admission, patients taking low- and high-dose opioids reported significantly greater pain severity and depression than those patients that were not taking this class of medication. Regardless of opioid status on admission, significant improvement was found for all outcomes following treatment and at six-months post treatment (as listed above and as measured using the instruments listed below in “assessments utilized”). Crisostomo et al evaluated patients in terms of three specific groups based on history of spinal surgery: fusion; non-fusion; and no surgical procedure. They found that patients that had undergone surgery were more likely to be taking opioids on admission (chi-square=8.92, P= 0.012, fusion 65.2%, nonfusion = 70%, no-surgery group = 48.4%). Pain severity and duration was highest in the fusion group. Patients that had undergone fusion were slightly more likely to drop out of the program (chisq=5.94, P=0.051; completers in the fusion group =78%, nonfusion group = 89%, and no-surgery group = 87%). Regardless of surgical status, patients showed significant and nearly equal improvement. In terms of medications the overall decrease in opioid use was 78.6%. Benzodiapezine decrease was 39.9%. The only significant difference in medication use at dismissal was for benzodiazepines, with more surgery patients using this class of drugs (chisq= 6.62, P = 0.037, fusion = 21.1%, nonfusion = 20.5%, no surgery = 9.6%). (Crisostomo 2008) Overall, successful opioid withdrawal and treatment completion was found for patients that had had lumbar spine surgery. Assessments utilized: Multi-dimensional Pain Inventory (MPI); SF-36; Center for Epidemiologic Studies-Depression Scale (CES-D); Pain catastrophizing scale (PCS).

Programs that do not emphasize opioid tapering

A more recent study of patient’s receiving workers’ compensation benefits in a program that did not stress opioid withdrawal found that at 6 months, 72.1% of opioid users returned to work versus 75.8% of non-opioid users, a non-significant difference. The mean dose of daily morphine equivalents was 28.63 mg (range 0.53 mg to 150 mg), which may limit the generalizability of the study. (Maclaren, 2006)



For general information, see Chronic pain programs.

Citalopram

See SSRIs (selective serotonin reuptake inhibitors).

Clonazepam

Not recommended. See Benzodiazepines.

Clonidine, intrathecal

There is no recommendation for its use as there is little evidence that this medication on its own provides long-term pain relief (when used in combination with opioids, approximately 80% of patients had < 24 months of pain relief) and no studies have investigated the neuromuscular, vascular or cardiovascular physiologic changes that can occur over long period of administration. Side effects include hypotension, and the medication should not be stopped abruptly due to the risk of rebound hypertension. The medication is FDA approved with an orphan drug intrathecal indication for cancer pain only. Clonidine is thought to act synergistically with opioids. Most studies on the use of this drug intrathecally for chronic non-malignant pain are limited to case reports. (Ackerman, 2003) Clonidine (Catapres) is a direct-acting adrenergic agonist prescribed historically as an antihypertensive agent, but it has found new uses, including treatment of some types of neuropathic pain.

Additional studies: One intermediate quality randomized controlled trial found that intrathecal clonidine alone worked no better than placebo. It also found that clonidine with morphine worked better than placebo or morphine or clonidine alone. (Ackermann, 2003) (Hassenbusch2, 2002) (Martin, 2001) (Raphael, 2002) (Roberts, 2001) (Siddall, 2000) (Taricco, 2006)

Clorazepate

Not recommended. See Benzodiazepines.

Cod liver oil

Not recommended for chronic pain. There is insufficient literature to support the use of cod liver oil for chronic pain.

Codeine (Tylenol with Codeine®)



Codeine is a schedule C-II controlled substance, but codeine with acetaminophen is a C-III controlled substance. It is similar to morphine. 60 mg of codeine is similar in potency to 600 mg of acetaminophen. It is widely used as a cough suppressant. It is used as a single agent or in combination with acetaminophen (Tylenol® with Codeine) and other products for treatment of moderate to severe pain. Codeine has disadvantages in that it is a pro drug that needs to be converted by the cytochrome P450 isoenzyme 2D6 to morphine, plus there are FDA alerts of ultra-rapid metabolism. (Ray, 2013) See also specific Codeine (Tylenol with Codeine®) listing for more information and references. See DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries,” Appendix F1, for dosing recommendations.

Adverse effects: Common effects include CNS depression and hypotension. Drowsiness and constipation occur in > 10% of cases. Codeine should be used in caution in patients with a history of drug abuse. Tolerance as well as psychological and physical dependence may occur. Abrupt discontinuation after prolonged use may result in withdrawal. (AHFS Drug Information, 2008) (Clinical Pharmacology, 2008) (Lexi-Comp, 2008)

Cognitive behavioral therapy

See sections on Behavioral interventions/ Cognitive Behavioral Therapy (CBT), Pyschological treatment , and Multi-disciplinary pain programs.







Cold lasers

See Low level laser therapy (LLLT).

Comorbid psychiatric disorders

Recommend screening for psychiatric disorders for patients with chronic unexplained pain, delayed recovery, poor response to treatment. Comorbid psychiatric disorders commonly occur in chronic pain patients. In a study of chronic disabling occupational spinal disorders in a large tertiary referral center, the overall prevalence of psychiatric disorders was 65% (not including pain disorder) compared to 15% in the general population. These included major depressive disorder (56%), substance abuse disorder (14%), anxiety disorders (11%), and axis II personality disorders (70%). (Dersh, 2006) When examined more specifically in an earlier study, results showed that 83% of major depression cases and 90% of opioid abuse cases developed after the musculoskeletal injury. On the other hand, 74% of substance abuse disorders and most anxiety disorders developed before the injury. This topic was also studied using the National Comorbidity Survey Replication (NCS-R), a national face-to-face household survey. (Dersh, 2002) See also Psychological evaluations.

Complex regional pain syndrome (CRPS)

See CRPS (complex regional pain syndrome).

Compound drugs


Not recommended as a first-line therapy. In general, commercially available, FDA-approved drugs should be given an adequate trial. If these are found to be ineffective or are contraindicated in individual patients, compound drugs that use FDA-approved ingredients may be considered. (Wynn, 2011) See specific entries for each ingredient. See also Topical analgesics, compounded. Pharmacy compounding has traditionally involved combining drug ingredients to meet the needs of specific patients for medications that are not otherwise commercially available, and it is undertaken on a patient-by-patient basis for patients who, for example, might be allergic to inactive ingredients in FDA-approved drugs or may need a different dosage strength or route of administration. Unlike commercially available drugs, these products are not approved by the FDA but rather are regulated by the state pharmacy board and state law governing the practice of pharmacy. The FDA does not regulate pharmacy-compounded products in recognition of the important public health function performed by traditional compounding. Recently, some pharmacies have been making and marketing stock compound drugs for the WC patient population. Among the FDA “Red Flags” for Enforcement Action on Compounded Drugs is: "Compounding drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to amounts compounded after receiving valid prescriptions." (FDA, 2011) Compound topical analgesics may provide relief by acting locally over the painful site with lower risk of systemic adverse effects on the gastrointestinal system and drug interactions than oral NSAIDs. The issues surrounding compound drugs are due to uncertainties regarding whether the products are medically appropriate and whether payments are reasonable, with the latter issue possibly also involving who dispenses the drug. Medical necessity should be based on the patient's needs combined with the medical and scientific evidence presented in ODG. See also Co-pack drugs; Medical foods; Physician-dispensed drugs; Repackaged drugs; & Topical analgesics, compounded.

Criteria for Compound drugs:

(1) Include at least one drug substance (or active ingredient) that is the sole active ingredient in an FDA-approved prescription drug, not including OTC drugs.

(2) Include only bulk ingredients that are components of FDA-approved drugs that have been made in an FDA-registered facility and have an NDC code.

(3) Is not a drug that was withdrawn or removed from the market for safety reasons.

(4) Is not a copy of a commercially available FDA-approved drug product.



(5) Include only drug substances that have been supported as safe and effective for the prescribed indication by the FDA-approval process and/or by adequate medical and scientific evidence in the medical literature. This would allow off-label usage when supported by medical evidence. See specific entries for each ingredient in ODG for the medical and scientific evidence. See also Topical analgesics, compounded. (Wynn, 2011)

(6) Any compounded product that contains at least one drug (or drug class) that is not recommended is not recommended. The use of compounded agents requires knowledge of the specific analgesic effect of each agent and how it will be useful for the specific therapeutic goal required. See also Topical analgesics, compounded. (Wynn, 2011)




Compounded topical analgesics

See Topical analgesics, compounded.

Constipation

See Opioid-induced constipation treatment.

ConZip (tramadol ER)



Not recommended as a first-line medication over generic tramadol ER. See also the general entry for Tramadol (Ultram®). In 2011 the FDA approved a capsule formulation of tramadol (ConZip), comprising an immediate-release tablet and sustained-release beads, for the management of moderate to moderately severe chronic pain. Vertical Pharmaceuticals will market Cipher Pharmaceuticals' CIP-Tramadol ER under the trade name ConZip (FDA, 2011) There are no clear advantages over generic tramadol. However, non-published studies (not rated in ODG) have shown that ConZip may have advantages as tramadol with IR and ER properties in one capsule, and ConZip can be administered without regard to meals. (FDA, 2012) If a patient is already stabilized on a long-acting tramadol, then the immediate-release component of the biphasic product has the potential to cause a higher than desired blood level of tramadol, which might impact a patient in a negative way. The clinical rationale for using a long-acting opioid is to maintain a stable blood level around-the-clock, so it is unclear how a biphasic formulation fits into chronic, around-the-clock opioid therapy. (FDA2, 2012) In addition, efficacy was demonstrated in only one of four studies that were conducted for approval of biphasic tramadol ER. (FDA3, 2012) See also Ryzolt (tramadol ER), another biphasic tramadol ER, but one which is available as a generic. Note: Because the ODG Formulary states that generic substitution is appropriate when FDA Generic Equivalency is Yes, Ryzolt is currently covered under the Tramadol ER generic listing, and users may dispense the most economical available option. Conzip has its own listing because the FDA has not approved any generic equivalents.

Co-pack drugs

Co-packs are convenience packaging of a medical food product and a generic drug into a single package that requires a prescription. There is no evidence to support the medical necessity of co-packs, as there are no high-quality medical studies to evaluate co-packs on patient outcomes. Labelers may create a new NDC for the co-pack. While the generic drug is FDA-approved, the co-pack of a medical food and FDA-approved drug is not unless the manufacturer obtains FDA approval for the product as a new drug. See specific entries for each ingredient in ODG. See also Compound drugs; Medical foods; Physician-dispensed drugs; Repackaged drugs.

Corticosteroids

See Oral corticosteroids; Injection with anaesthetics and/or steroids.

CRPS (complex regional pain syndrome)

See CRPS, pathophysiology (clinical presentation & diagnostic criteria); CRPS, diagnostic tests; CRPS, treatment; CRPS, sympathetic blocks (therapeutic); CRPS, medications.

CRPS, diagnostic criteria

See CRPS, pathophysiology (clinical presentation & diagnostic criteria).

CRPS, diagnostic tests

Recommend assessment of clinical findings as the most useful method of establishing the diagnosis. See CRPS, pathophysiology (clinical presentation & diagnostic criteria). Specific procedures are not generally recommended, except as indicated below. A gold standard for diagnosis of CRPS has not been established and no test has been proven to diagnose this condition. Assessment of clinical findings is currently suggested as the most useful method of establishing the diagnosis. The following procedures have been suggested for use as additional tools for diagnosis, with use based on the patient’s medical presentation. Recent CRPS guidelines do not discuss these tests in general but general information is available at the Reflex Sympathetic Dystrophy Syndrome Association website. (Aker, 2008) (Harden, 2013)

Imaging studies

Triple-phase bone scans (three-phase bone scintigraphy or TPBS): Recommended for select patients in early stages to help in confirmation of the diagnosis. Routine use is not recommended. The three phases are referred to as blood flow (first phase injection), blood pool (second phase at approx 2 minutes post injection), and delayed (third phase at approx 3 hours). The diagnosis is suggested when the blood flow and blood pool images show diffuse asymmetric uptake, or when the delayed image indicates increased asymmetric periarticular uptake. There is research to suggest that the delayed phase is the most sensitive for the diagnosis. (Pankaj, 2006) (Wüppenhorst, 2010) Osteoporosis is seen at a later duration after the diagnosis is made. A positive test is not necessarily concordant with the presence or absence of CRPS I and the diagnostic value of a positive test for CRPS is considered low from the view point of the Budapest research criteria versus previously used criteria that were less restrictive. (Moon 2012) (Ringer, 2012) (Lee, 1995) Extremely variable levels of sensitivity are reported with use (in one case as low as 14%). (Schurmann 2007) The sensitivity of the test is less than its specificity and the former declines with increasing duration of CRPS. Suggestion has been made that TPBS it is most useful in the early duration after diagnosis (4-6 months). (Wüppenhorst, 2010)

Conditions in which similar findings are noted: Similar findings can occur with the following pathology: immobilization; denervation; stroke; venous, arterial and/or lymphatic obstruction; and cellulitis. There is also a report of increased articular uptake produced by self-application of a tourniquet on the wrist with resolution of symptoms once a diagnosis of Munchausen’s syndrome was made. (Rodriguez-Moreno, 1990)

According to the ODG UR Advisor, CPT 78315, 3 phase bone imaging, had a WC Frequency of 23.47% for ICD9 code 337.2, Reflex sympathetic dystrophy (CRPS I), and a WC Frequency of 7.84% for ICD9 code 355, Mononeuritis of lower limb (CRPS II). (ODG-UR, 2011)



MRI: Not specifically recommended for the diagnosis of CRPS due to low specificity of findings. CRPS findings in hand pathology include bone marrow edema of the carpals, skin edema, uptake of the skin, joint effusion and intraarticular uptake. (Schurmann, 2007)

Plain film x-rays: Not specifically recommended for the diagnosis of CRPS alone. CRPS findings include soft tissue swelling, osteopenia/osteoporosis (generally patchy earlier in the disease and more generalized at a later duration), cortical bone resorption and articular erosion. These findings can also be seen with disuse atrophy. Radiographic findings are not considered a screening procedure as changes appear later in the disease, and findings may be seen in other conditions. X-rays of both extremities should be performed for comparison. The procedure may be most useful to evaluate for missed fractures. (Cappello 2012)

Temperature measures: Temperature differences are dynamic in patients with CRPS due to variables such as intraindividual shifts, with a measure at a single point of time producing an almost random result (in terms of whether the affected limb will be warmer or colder than the non-affected extremity). Skin temperature also appears to be affected by duration of disease, with some research suggesting that the affected extremity is warmer in early stages. Caution is advised since environmental conditions can affect test results. An additional problem is that temperature (and color) changes can be produced with short-term dependency, immobility and vascular or vasomotor diseases. With the addition of cold water immersion at 15 degrees C for 15 minutes the submerged hand remains cooler at 60 minutes. (Wasner, 2001) (Wasner, 2002) (Wasner, 2010) (Singh, 2006) (Marinus, 2011) Skin temperature can be measured using a contact method, although this can be painful.

Infrared thermometry: Recommended in select patients for objective measure of temperature difference. Sensitivity is poor with better specificity. (Sherman , 1994)

Infrared thermography: Not recommended. There is insufficient evidence to support the routine use of thermography for diagnosis of CRPS. (Krumova , 2008) (Schürmann, 2007)

Laser Doppler flowmetry: Not recommended. Use is primarily for research and there is insufficient evidence to support routine clinical use. (Murray, 2004) (Aker, 2008)

Sudomotor measures: Most formal diagnostic tests for this are laboratory based and not generally recommended. Tests include (1) the iontophoretic quantitative sudomotor axon reflex test (QSART), (2) the sialastic sweat imprint method, (3) the thermoregulatory sweat test (TST), (4) sympathetic skin response and related electrodermal activity, (5) sympathetic skin resistance and selective tissue conductance, (6) quantitative sensory testing (QST), (7) resting sweat output (RSO).

Nerve conduction velocity: Can be considered as recommended to investigate the presence of nerve injury/ neuropathy and differentiate between CRPS I and II. (Aker, 2008)

Tests considered experimental and not recommended: (1) Phentolamine injection; (2) Bone density testing; (3) Positron emission tomography (PET); (4) Single photon emission tomography (SPECT).

Skin biopsy for evidence of small nerve fiber degeneration: Not recommended. While small nerve fiber pathology has been a causal factor for CRPS, this remains to be established. It should also be noted that other causes of neuropathic pain are frequently associated with loss of C-fiber peripheral terminals, making the specificity of these tests with respect to CRPS questionable. Common causes of small fiber polyneuropathy include diabetes, hematological malignancies, autoimmune conditions, infections, toxins (including medications) and mutations. Oaklander et al. have indicated this test is not promising for routine clinical analysis. (Devigilli, 2008) (Oaklander, 2006) (Marinus, 2011) (Oaklander, 2013)

Sympathetic nerve blocks, diagnostic: Recommended in a limited role for diagnosis of sympathetically mediated pain with the understanding that sympathetic blocks are not specific for CRPS. See Sympathetically maintained pain (SMP). Less than 1/3 of patients with CRPS are likely to respond to sympathetic blockade. There are no signs or symptoms to predict block success. The use of sympathetic blocks for diagnostic purposes in CRPS I is based on previous hypotheses concerning involvement of the sympathetic nervous system as a pathophysiologic cause of this disease. Monitoring for sympathetic and sensory function after the block is required. In the upper extremity interpretation of up to 73% of blocks cannot be made due to compounding factors. (Krumova, 2011) (Schürmann, 2001)

Interpretation: A current suggestion of adequate block is one that demonstrates an adequate and sustained increase in skin temperature (≥ 1.5° C and ≥ 90 minutes), without evidence of thermal or tactile sensory blocks. (Krumova, 2011) (Schürmann, 2001) An assessment for false-positives (unintentional sensory blocks) and false-negatives (insufficient sympathetic block) should be made.

See also CRPS, sympathetic blocks (therapeutic).



Recommendations (based on consensus guidelines) for an adequate CRPS evaluation

(1) There should be evidence that the Budapest (Hardin) criteria have been evaluated for and fulfilled.

(2) There should be evidence that all other diagnoses have been ruled out. A diagnosis of CRPS should not be accepted without a documented and complete differential diagnostic process completed as a part of the record.

(3) If a sympathetic block is utilized for diagnosis, there should be evidence that this block fulfills criteria for success including that skin temperature after the block shows sustained increase (≥ 1.5° C and/or an increase in temperature to > 34° C) without evidence of thermal or tactile sensory block. Evidence of a Horner’s response to upper extremity blocks should be documented. The use of sedation with the block can influence results, and this should be noted. (Krumova, 2011) (Schürmann, 2001)



CRPS, ketamine subanesthetic infusion

Not recommended. See Ketamine.

CRPS, medications

Recommended only as indicated below. Most medications have limited effectiveness, and recommendations are primarily based on extrapolation from neuropathic pain medication guidelines. A reason given for the paucity of medication studies is the absence of a gold-standard diagnostic test for CRPS and lack of uniformly accepted diagnostic criteria. (Ribbers, 2003) (Quisel2, 2005) (Harden, 2013)

1. Regional inflammatory reaction: Commonly used drugs are NSAIDS, corticosteroids and free-radical scavengers. There is some evidence of efficacy for topical DMSO cream, IV bisphosphonates and limited courses of oral corticosteroids. Corticosteroids are most effective earlier in the condition when positive response is obtained with sympathetic blocks. NSAIDs are recommended but no trials have shown effectiveness in CRPS-I, and they are recommended primarily in early or very late stages. (Stanton-Hicks, 2004) (Sharma, 2006) Because long-term controlled studies have not been conducted, DMSO should be considered investigational and used only after other therapies have failed. (FDA, 2010)

2. Stimulus-independent pain: The use of antidepressants (primarily tricyclics and SNRIs), anticonvulsants (with the most support for gabapentin), and opioids has been primarily extrapolated based on use for other neuropathic pain disorders. There are no long-term studies demonstrating efficacy of opioids as treatment for CRPS. See Antidepressants for neuropathic pain; & Anticonvulsants for chronic pain; . Current literature does not support the use of clonidine. (Hsu, 2009) (Harden, 2013)

3. Stimulus-evoked pain: treatment is aimed at central sensitization. With NMDA receptor antagonists (ketamine and amantadine) convincing controlled trials are lacking, and these drugs are recognized for their side effects. See Ketamine.

4. Sympathetically maintained pain (SMP): See IV regional sympathetic blocks (for RSD/CRPS); CRPS, sympathetic block (therapeutic); CRPS, treatment.

5. Treatment of bone resorption and resultant pain with bisphosphonate-type compounds and calcitonin. Bisphosphonates include alendronate, ibandronate, risedronate, zoledronate, etidronate, and pamidronate. There is no research on the newer longer-lasting drugs that are administered by periodic IV infusion (ibandronate, zoledronate and pamidronate). Significant improvement has been found in limited studies with intravenous alendronate. Alendronate (Fosamax®) given in oral doses of 40 mg a day (over an 8-week period) produced improvements in pain, pressure tolerance and joint mobility. There has also been evidence of improvement of pain with pamidronate. Osteopenia was not an outcome. (Manicourt, 2004) See also Bisphosphonates. Mixed results have been found with intranasal calcitonin (Miacalcin®). (Sahin, 2005) (Appelboom, 2002) (Rowbathan, 2006) (Sharma, 2006) (Perez, 2001) The mechanism of action of these drugs is uncertain.

6. Treatment of dystonia: Oral baclofen is a first-line option. Benzodiazepines and long-term use of muscle relaxants such as cyclobenzaprine are not recommended. (Harden, 2013)

7. Treatment considered experimental and not recommended: IVIG, Sildenafil



CRPS, pathophysiology (clinical presentation & diagnostic criteria)

Recommend using a combination of criteria as per the revised Budapest (Harden) criteria as indicated below to make this diagnosis. There are no objective gold-standard diagnostic criteria for CRPS I or II. The diagnosis is based on what are predominately subjective criteria which are shared by many other diseases (see Differential diagnosis below). Current diagnostic criteria specifically indicate that there can be no other diagnosis that better explains signs and symptoms. The importance of establishing a correct diagnosis and to prevent potentially harmful and/ or unwarranted treatment cannot be emphasized enough.

Pathophysiology: Multiple hypotheses have been promoted to explain both CRPS I and II. These include peripheral mechanisms that are inflammatory, altered cutaneous innervation after injury, peripheral sensitization, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, central mechanisms, and psychophysiological interactions. Lab findings have included signs of increased neurogenic inflammation, small fiber neuropathy, tissue hypoxia and altered immune response. Most researchers feel that the interaction between these multiple pathways is what explains the heterogeneity of presentation and course. (Marinus, 2011) (Bruehl, 2010) The associations of non-dermatomal patterns of pain, unusual movement disorders and somatovisceral dysfunction have been particularly difficult to explain. In addition, the objective physical signs of CRPS, including imaging, can be created with disuse and or physical manipulation. (Cooper, 2013) (Bruehl, 2010) (Harden, 2013) (Goebel, 2012) (Rodriguez-Moreno, 1990)

CRPS Criteria

A. CRPS-I (previously referred to as reflex sympathetic dystrophy RSD):

The three criteria generally identified in the literature include those suggested by Veldman et al., those originally suggested by the IASP, and a further modification of the latter referred to as the Budapest (Harden) criteria. Agreement between the three sets is poor, with the most frequent diagnoses made using the original IASP criteria and the lowest using the Budapest criteria. A major problem is that depending on the diagnostic criteria utilized, comparability of studies is compromised. The risk of misdiagnosis increases depending on the point of reference.



Veldman Criteria: (1) At least four out of five signs or symptoms must be present (pain, difference in skin color, edema, difference in skin temperature and active range of motion); (2) Signs and symptoms are present in an area larger than might be expected of initial trauma; (3) An increase of signs and/or symptoms occur during or after exercise. (Veldman, 1993)

The IASP (International Association for the Study of Pain) early on defined this diagnosis as a variety of painful conditions following injury which appear regionally, having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event, often resulting in significant impairment of motor function, and showing variable progression over time. (Stanton-Hicks, 1995) Diagnostic criteria defined by IASP in 1994 were the following: (1) The presence of an initiating noxious event or cause of immobilization that leads to development of the syndrome; (2) Continuing pain, allodynia, or hyperalgesia which is disproportionate to the inciting event and/or spontaneous pain in the absence of external stimuli; (3) Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the pain region; & (4) The diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain or dysfunction. Criteria 2-4 must be satisfied to make the diagnosis. These criteria were found to be able to pick up a true positive with few false negatives (sensitivity 99% to 100%), but their use resulted in a large number of false positives (specificity range of 36% to 55%). (Bruehl, 1999) (Galer, 1998) Up to 37% of patients with painful diabetic neuropathy may meet the clinical criteria for CRPS using the original diagnostic criteria. (Quisel, 2005)

The Budapest (Harden) Criteria represent a revision of the above IASP Criteria. There are two versions of these proposed diagnostic criteria. A diagnostic version was developed to maximize sensitivity (identify true positive cases) with adequate specificity (i.e. avoiding a false positive diagnosis). A research version was developed to more equally balance sensitivity and specificity. The diagnostic criteria are the following: (1) Continuing pain, which is disproportionate to any inciting event; (2) Must report at least one symptom in three of the four following categories: (a) Sensory: Reports of hyperesthesia and/or allodynia; (b) Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry; (c) Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry; (d) Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin); (3) Must display at least one sign at time of evaluation in two or more of the following categories: (a) Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement); (b) Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry; (c) Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry; (d) Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin); (4) There is no other diagnosis that better explains the signs and symptoms. (Harden, 2007) (Harden, 2010) This diagnostic version produces a sensitivity of 85% and specificity of 69%. The research version requires reporting of at least one symptom in each of the four categories (vs. in three of the four in the diagnostic version). This provides a sensitivity of 70% and specificity of 96%. (Harden, 2013)

AMA Guidelines: This group puts a strong emphasis on the differential diagnostic process. They point out that there is no gold standard diagnostic feature which reliably distinguishes the diagnosis of CRPS for presentations that clearly are not CRPS. They state, “Scientific findings have actually indicated that whenever this diagnosis is made, it is probably incorrect.” (AMA Guides, 6th ed.)

Other authors have questioned the usefulness of diagnostic testing over and above history and physical findings. (Quisel, 2005) (Yung, 2003) (Perez2, 2005) It is suggested that a negative diagnostic test should not question a clinically typical presentation of CRPS and should not delay treatment. (Birklein, 2005)



B. CRPS-II (previously referred to as causalgia):

Nerve damage may be detected by electrodiagnostic testing, but pain is not contained to that distribution. The diagnosis can also be made where there is evidence of a major nerve lesion. (Stanton-Hicks, 1995) (Harden, 2013) CRPS I and II appear to be clinically similar. (Bruehl, 1999) (Oaklander, 2009) CRPS-II is defined by the IASP as: (1) The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve; (2) Evidence at some time of edema, changes in skin blood flow, and/or abnormal sudomotor activity in the region of pain; & (3) The diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.



C. CRPS not otherwise specified (CRPS-NOS):

This diagnosis is not endorsed by ODG. This is a subgroup of patients who do not fully meet the criteria but whose signs and symptoms cannot be explained better by another diagnosis. This subtype was added by the Reflex Sympathetic Dystrophy Syndrome Association to capture any patients previously diagnosed with CRPS who now did not meet criteria.



Recent research into CRPS subtypes

Current research suggests there is little evidence for “stages” of CRPS (historically noted as three sequential stages classified as acute, dystrophy and atrophy). Research now points to distinct subtypes. Subtype 1 is a relatively limited syndrome in which vasomotor signs predominate. Subtype 2 is a relatively limited syndrome in which neuropathic pain and/or sensory abnormalities predominate. This subtype is thought to be consistent with CRPS II (causalgia) based on electrodiagnostic changes, but EDX is often not sensitive. A third subtype consists of a florid CRPS picture with the greatest predominance of motor/trophic changes with possible osteopenic changes on bone scan. (Harden, 2013) Other authors suggests that subtypes should be made as acute (early) and late (chronic) with a third group labeled as chronic, refractory CRPS. (Zyluk, 2013)



Controversy with establishing the diagnosis:

Differential Diagnoses: It is suggested that in the absence of a differential diagnostic evaluation for patients with a suggested diagnosis of CRPS, management can be abortive and iatrogenic harm may follow. These diagnoses include peripheral neuropathies, infectious processes, inflammatory and vascular disorders, (including dysvascular states in smokers, thrombosis, and arterial insufficiency), and regional musculoskeletal disorders. (Quisel2, 2005) (Stanton-Hicks, 2006) They also include the following conditions: Undetected/unstable fracture; Post-herpetic neuralgia; Motor neuron disease; Diabetic neuropathy; Soft tissue infection; Subclinical nerve entrapments; Atypical nerve compressions; Compartment syndrome; Entrapment neuropathy; Arthritis; Lymphatic or venous obstruction; Raynaud’s disease; Rheumatoid arthritis and other rheumatologic disease; Seronegative arthritis; Malignant tumors. (van Eijs, 2011) (Goebel, 2012) (Stanton-Hicks, 2004) A suggested diagnosis of CRPS indicates the urgent need for extensive exploration of the differential diagnosis. (Borchers, 2013)



Immobilization: Disuse has also been suggested as a differential diagnosis as the clinical signs (including imaging) found can be produced with immobilization. Complications of casting an extremity include joint contractures, compression neuropathy, dystonia, regional osteoporosis, movement-induced pain and swelling. All of these symptoms are similar to findings attributed to CRPS. (Terkelsen, 2008) (Harden, 2013) (Janig, 2004) (Akeson, 1987) (Veldhuizen, 1993) (Okun, 2002)

Immobilization in conjunction with psychological factors: Disuse in the presence of pre-existing psychopathology is proposed as a link producing a CRPS presentation. Extreme fear of pain can lead to immobilization of the involved extremity. (de Mos, 2009) (Harden, 2013)

The relation of psychiatric and psychological factors and CRPS: Researchers have suggested that likely differential diagnoses for CRPS should include (1) somatoform disorder, and (2) malingering. Psychiatric overlay has been strongly suggested, particularly in literature dealing with dystonia, and a contribution of functional psychophysiologic links to development of CRPS has not been ruled out. (Bruehl, 2010) (Hawley, 2011) (Verdugo, 2000) (Ochoa, 2010) (Lang, 2010) Theoretical links have been proposed suggesting psychological factors could potentially influence CRPS development but additional prospective tests are required to tests these hypotheses. An actual association between psychosocial factors and CRPS remains controversial, in part due to lack of methodological high-quality studies. (de Mos, 2009) (Beerthuizen, 2009) A recent prospective cohort study revealed no empirical evidence to support a diagnosis of CRPS I patients as psychologically different in a Dutch population using the Symptom Checklist-90. The few prospective studies that are available do not point to a unique CRPS I personality or psychosocial pattern. (Marinus, 2011) (Beerthuizen, 2011) (de Mos, 2009) (Bruehl, 2010)

Risk factors: Financial gain (such as that involved with litigation) has been found to increase the risk of CRPS. (Scarano, 1998) (Goebel, 2012)

See also CRPS, treatment; Sympathetically maintained pain (SMP); CRPS, medications; CRPS, prevention; & CRPS, sympathetic blocks (therapeutic)



CRPS, prevention

See CRPS, pathophysiology (clinical presentation & diagnostic criteria).

CRPS, spinal cord stimulators (SCS)

Recommended as indicated below. Spinal cord stimulators (SCS) should be offered only after careful counseling and patient identification and should be used in conjunction with comprehensive multidisciplinary medical management. SCS use has been associated with pain reduction in studies of patients with CRPS. (Kemler, 2000) (Kemler, 2004) (Kemler, 2008) CRPS patients implanted with SCS reported pain relief of at least 50% over a median follow-up period of 33 months. (Taylor, 2006) Moreover, there is evidence to demonstrate that SCS is a cost-effective treatment for CRPS-I over the long term. (Stanton-Hicks, 2006) (Mailis-Gagnon-Cochrane, 2004) (Kemler, 2002) Permanent pain relief in CRPS-I can be attained under long-term SCS therapy combined with physical therapy. (Harke, 2005) See Spinal cord stimulators (SCS).

For average hospital LOS if criteria are met, see Hospital length of stay (LOS).



CRPS, sympathectomy

Not recommended. The practice of surgical, chemical and radiofrequency sympathectomy is based on poor quality evidence, uncontrolled studies and personal experience. Furthermore, complications of the procedure may be significant, in terms of both worsening the pain or producing a new pain syndrome; and abnormal forms of sweating (compensatory hyperhidrosis and pathological gustatory sweating). Therefore, more clinical trials of sympathectomy are required to establish the overall effectiveness and potential risks of this procedure. (Furlan, 2000) (Mailis-Cochrane, 2003) Sympathectomy is destruction of part of the sympathetic nervous system, and it is not generally accepted or widely used. Long-term success with this pain relief treatment is poor. Indications: Single extremity CRPS-I or SMP; distal pain only (should not be done if the proximal extremity is involved). Local anesthetic Stellate Ganglion Block or Lumbar Sympathetic Block consistently gives 90 to 100 percent relief each time a technically good block is performed (with measured rise in temperature). The procedure may be considered for individuals who have limited duration of relief from blocks. Permanent neurological complications are common. (State, 2002)

For average hospital LOS if criteria are met, see Hospital length of stay (LOS).



CRPS, sympathetic blocks (therapeutic)

Recommend local anesthetic sympathetic blocks for limited, select cases, as indicated below. Not recommend IV regional anesthesia blocks.

Local anesthetic sympathetic blocks:

Recommended for limited, select cases, primarily for diagnosis of sympathetically mediated pain and therapeutically as an adjunct to facilitate physical therapy/ functional restoration. When used for therapeutic purposes the procedure is not considered a stand-alone treatment. The role of sympathetic blocks for treatment of CRPS is largely empirical (with a general lack of evidence-based research for support) but can be clinically important in individual cases in which the procedure ameliorates pain and improves function, allowing for a less painful “window of opportunity” for rehabilitation techniques. (Harden, 2013) Use of sympathetic blocks should be balanced against the side effect ratio and evidence of limited response to treatment. See CRPS, diagnostic tests.



IV regional anesthesia: Not recommended due to lack of evidence for use. This procedure is a technique that allows placement of medications directly in the effected extremity but current literature indicates efficacy is poor. (Harden, 2013) There is no role for IV diagnostic blocks with phentolamine or IVRA with guanethidine. Other procedures include IV regional blocks with lidocaine, lidocaine-methyl-prednisolone, droperidol, ketanserin, atropine, bretylium clonidine, and reserpine. If used, there must be evidence that current CRPS criteria have been met and all other diagnoses have been ruled out. Evidence of sympathetically mediated pain should be provided (see the recommendations below). The reason for the necessity of this procedure over-and-above a standard sympathetic block should also be provided. (Perez, 2010) (Harden, 2013) (Tran, 2010) See also CRPS, treatment.

General information on sympathetic procedures

Current literature: A recent study indicated that there was low quality literature to support this procedure (some evidence of effect, but conclusions were limited by study design, divergent CRPS diagnostic criteria, differing injection techniques and lack of consistent criteria for positive response). Results were inconsistent and/or extrapolation of questionable reliability with inconclusive evidence to recommend for or against the intervention. (Dworkin, 2013) Other studies have found evidence non-conclusive for this procedure or that low-quality evidence showed this procedure was not effective. (O’Connell, 2013) (Tran, 2010) The blocks are thought to be most beneficial when used early in the disease as an adjunct to rehabilitation with physical or occupational therapy. No controlled trials have shown any significant benefit from sympathetic blockade. (Dworkin 2013) (O’Connell, 2013) (Tran, 2010) (van Eijs, 2012) (Perez, 2010) (van Eijs, 2011) (Nelson, 2006) (Varrassi, 2006) (Cepeda, 2005) (Hartrick, 2004) (Grabow, 2005) (Cepeda, 2002) (Forouzanfar, 2002) (Sharma, 2006)

Historical basis for use: The use of sympathetic blocks for diagnostic and therapeutic purposes in the management of CRPS is based on a previous hypothesis concerning the involvement of the sympathetic nervous system in the pathophysiological mechanism of the disease. (van Eijs, 2012) It has been determined that a sympathetic mechanism is only present in a small subset of patients, and less than 1/3 of patients with CRPS are likely to respond to sympathetic blockade. See Sympathetically maintained pain (SMP).

Predictors of response: Researchers have suggested the following are predictors of poor response to blocks: (1) Long duration of symptoms prior to intervention; (2) Elevated anxiety levels; (3) Poor coping skills; (4) Litigation; (5) Allodynia and hypoesthesia. At this time there are no symptoms or signs that predict treatment success. (Hartrick, 2004) (Nelson, 2006) (van Eijs, 2012)

Interpretation of block results: There is a lack of consensus in terms of defining a successful sympathetic block. Based on consensus, a current suggestion of successful block is one that demonstrates an adequate and sustained increase in skin temperature (≥ 1.5° C and/or an increase in temperature to > 34° C) without evidence of thermal or tactile sensory block. A Horner’s sign is should be documented for upper extremity blocks.

Recommendations (based on consensus guidelines) for use of sympathetic blocks (diagnostic block recommendations are included here, as well as in CRPS, diagnostic tests):

(1) There should be evidence that all other diagnoses have been ruled out before consideration of use.

(2) There should be evidence that the Budapest (Harden) criteria have been evaluated for and fulfilled.

(3) If a sympathetic block is utilized for diagnosis, there should be evidence that this block fulfills criteria for success including that skin temperature after the block shows sustained increase (≥ 1.5° C and/or an increase in temperature to > 34° C) without evidence of thermal or tactile sensory block. Documentation of motor and/or sensory block should occur. This is particularly important in the diagnostic phase to avoid overestimation of the sympathetic component of pain. A Horner’s sign should be documented for upper extremity blocks. The use of sedation with the block can influence results, and this should be documented if utilized. (Krumova, 2011) (Schurmann, 2001)

(4) Therapeutic use of sympathetic blocks is only recommended in cases that have positive response to diagnostic blocks and diagnostic criteria are fulfilled (See #1-3). These blocks are only recommended if there is evidence of lack of response to conservative treatment including pharmacologic therapy and physical rehabilitation.

(5) In the initial therapeutic phase, maximum sustained relief is generally obtained after 3 to 6 blocks. These blocks are generally given in fairly quick succession in the first two weeks of treatment with tapering to once a week. Continuing treatment longer than 2 to 3 weeks is unusual.

(6) In the therapeutic phase repeat blocks should only be undertaken if there is evidence of increased range of motion, pain and medication use reduction, and increased tolerance of activity and touch (decreased allodynia) is documented to permit participation in physical therapy/ occupational therapy. Sympathetic blocks are not a stand-alone treatment.

(7) There should be evidence that physical or occupational therapy is incorporated with the duration of symptom relief of the block during the therapeutic phase.

(8) In acute exacerbations of patients who have documented evidence of sympathetically medicated pain (see #1-3), 1 to 3 blocks may be required for treatment.

(9) A formal test of the therapeutic blocks should be documented (preferably using skin temperature).



(Burton, 2006) (Stanton-Hicks, 2004) (Stanton-Hicks, 2006) (International Research Foundation for RSD/CRPS, 2003) (Colorado, 2006) (Washington, 2002) (Rho, 2002) (Perez, 2010) (van Eijs, 2011)

CRPS, treatment

Recommend hierarchy of options as indicated below. The goal is to improve function. There are no evidence-based treatment guidelines, but several groups have begun to organize treatment algorithms that are consensus based. There is currently no intervention for CRPS that can be considered to be supported by strong evidence of efficacy. (Ribbers, 2003) (Stanton-Hicks, 2006) (O’Connell, 2013) Interdisciplinary management is recommended emphasizing functional restoration. (Harden, 2013) (Singh, 2004) (Albazaz, 2008) (Hsu, 2009)

1. Rehabilitation: (a) Early stages: Build a therapeutic alliance. Analgesia, encouragement and education are key. Physical modalities include desensitization, isometric exercises, resisted range of motion, and stress loading. If not applied appropriately, PT may temporarily increase symptoms, particularly if too aggressive. (b) Next steps: Increase flexibility with introduction of gentle active ROM and stretching (to treat accompanying myofascial pain syndrome). Other interventions to enhance participation in rehabilitation may include muscle relaxants, trigger point injections and electrical stimulation (based on anecdotal evidence). Edema control may also be required (elevation, retrograde sympathetic blocks, diuretics and adrenoceptor blockers when sympathetically maintained pain-SMP is present). (c) Continued steps: Continue active ROM, stress loading, scrubbing techniques, isotonic strengthening, general aerobic conditioning, and postural normalization. (d) Final steps: Normalization of use, assessment of ergonomics, and posture and modifications at home and work.

2. Psychological treatment: Focused on improved quality of life, development of pain coping skills, cognitive-behavioral therapy, and improving facilitation of other modalities. (a) Early stages: Education. (b) Next steps: Clinical psychological assessment, after 6 to 8 weeks, identification of stressors, and identification of comorbid Axis I psychiatric disorders (depression, anxiety, panic and post-traumatic stress).

3. Pain management:

Pharmacological treatment: See CRPS, medications.

Invasive treatment: The role of sympathetic blocks is largely empirical with lack of solid evidence. See CRPS, sympathetic blocks, (therapeutic) for more specific information and criteria for use of sympathetic treatment.

Local anesthetic sympathetic blocks: Recommended for limited, select cases, primarily for diagnosis of sympathetically mediated pain and therapeutically as an adjunct to facilitate physical therapy/ functional restoration. When used for the latter the procedure is not considered a stand-alone procedure. The role of sympathetic blocks for treatment of CRPS is largely empirical (with a general lack of evidence-based research for support) but can be clinically important in individual cases in which the procedure ameliorates pain and improves function, allowing for a less painful “window of opportunity” for rehabilitation techniques. (Harden, 2013)

Sympathectomy: Not recommended. See CRPS, sympathectomy.

IV regional anesthesia: Not recommended due to lack of evidence for use. See CRPS, sympathetic blocks, (therapeutic); Intravenous regional sympathetic blocks (for RSD/CRPS).

Epidural infusions for sympathetic blockade: Not recommended due to lack of evidence for use and high risk of complications including infection. There is one randomized controlled trial that reported improvement. A study that included both randomized and open label design (26 patients) using clonidine showed pain relief, but the authors considered this experimental and the study has not been repeated. Infections occurred in 6/19 patients who ultimately received the treatment. (Rauck, 1993)

Brachial plexus blocks: Not recommended due to the lack of evidence for use and risk of complications including infection, intravascular injection, pneumothorax, and phrenic nerve paralysis. (Harden, 2013) (Tran, 2010)

Intrathecal drugs: Opioids are not recommended. Baclofen may play a limited, end-stage role for treatment for patients with dystonia, the area which the limited research addresses. The first study was conducted in 7 patients using IASP criteria. Six of these received a pump. Greater effect was found in the arms than legs. When followed for a year, the largest improvement was noted in the first three months with stabilization around a one year period. Lack of responsiveness to intrathecal baclofen declined in 30% of patients once delivery was switched from external to implantable treatment. A large number of adverse events were noted with the most common being post-dural headache. In this second study the authors indicated that to enhance therapeutic potential, methods to improve patient selection and catheter-pump integrity were warranted. Increasing the infusion rate did not result in improvement of dystonia. The authors also note that significant improvement in global intense pain, sharp pain, dull pain and deep pain occurred in the first six months of this open design, but after this period the scores leveled despite further improvement of dystonia and continued ITB dose escalation. (van der Plas, 2013) (van Rijn, 2009)

Spinal Cord Stimulator: See CRPS, spinal cord stimulators.

See also CRPS, pathophysiology (clinical presentation & diagnostic criteria); CRPS, medications; CRPS, sympathetic blocks (therapeutic); Intravenous regional sympathetic blocks (for RSD/CRPS); & Sympathetically maintained pain (SMP).



Curcumin (turmeric)

Not recommended for chronic pain. There is insufficient literature to support the use of curcumin for chronic pain.

Current perception threshold (CPT) testing

Not recommended. Current perception threshold testing is considered experimental or investigational, as there is inadequate scientific literature to support any conclusions regarding the effects of this testing on health outcomes..

Cyclobenzaprine (Flexeril®)

Recommended as an option, using a short course of therapy. See Medications for subacute & chronic pain for other preferred options. Cyclobenzaprine (Flexeril®) is more effective than placebo in the management of back pain; the effect is modest and comes at the price of greater adverse effects. The effect is greatest in the first 4 days of treatment, suggesting that shorter courses may be better. (Browning, 2001) Treatment should be brief. There is also a post-op use. The addition of cyclobenzaprine to other agents is not recommended. (Clinical Pharmacology, 2008) Cyclobenzaprine-treated patients with fibromyalgia were 3 times as likely to report overall improvement and to report moderate reductions in individual symptoms, particularly sleep. (Tofferi, 2004) Note: Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline. See Antidepressants. Cyclobenzaprine is associated with a number needed to treat of 3 at 2 weeks for symptom improvement in LBP and is associated with drowsiness and dizziness. (Kinkade, 2007) Cyclobenzaprine is a skeletal muscle relaxant and a central nervous system (CNS) depressant that is marketed as Flexeril by Ortho McNeil Pharmaceutical. See also Muscle relaxants (for pain), Cyclobenzaprine listing.

Cymbalta® (duloxetine)

Cymbalta® is the brand name for duloxetine, and it is supplied by Eli Lilly and Company. Duloxetine is an antidepressant in the class called Selective serotonin and norepinephrine reuptake inhibitors (SNRIs). See Duloxetine (Cymbalta®).

Cytochrome p450 testing

See Cytokine DNA testing.

Cytokine DNA testing

Not recommended. There is no current evidence to support the use of cytokine DNA testing for the diagnosis of pain, including chronic pain. Scientific research on cytokines is rapidly evolving. There is vast and growing scientific evidence base concerning the biochemistry of inflammation and it is commonly understood that inflammation plays a key role in injuries and chronic pain. Cellular mechanisms are ultimately involved in the inflammatory process and healing, and the molecular machinery involves cellular signaling proteins or agents called cytokines. Given rapid developments in cytokine research, novel applications have emerged and one application is cytokine DNA signature testing which has been used as a specific test for certain pain diagnoses such as fibromyalgia or complex regional pain syndrome. The specific test for cytokine DNA testing is performed by the Cytokine Institute. (www.cytokineinstitute.com) Two articles were found on the website. However, these articles did not meet the minimum standards for inclusion for evidence-based review. (Gavin, 2007) (Gillis, 2007) In a research setting, plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis. (Kokkonen, 2010) See also Genetic testing for potential opioid abuse.

Darvon® (propoxyphene)

See Propoxyphene (Darvon®).

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