Rule 17, exhibit 9

MEDICATIONS and Medical Management There is no single formula for pharmacological treatment of patients with chronic nonmalignant pain. A thorough medication history, including use of alternative and over the counter medications, should be performed at the time of the initial visit and updated periodically. The medication history may consist of evaluating patient refill records through pharmacies to determine if the patient is appropriately taking their prescribed regimen. Appropriate application of pharmacological agents depends on the patient’s age, past history (including history of substance abuse), drug allergies and the nature of all medical problems. It is incumbent upon the healthcare provider to thoroughly understand pharmacological principles when dealing with the different drug families, their respective side effects, drug interactions, bioavailability profiles, and primary reason for each medication’s usage. Patients should be aware that medications alone are unlikely to provide complete pain relief. In addition to pain relief, a primary goal of drug treatment is to improve the patient’s function as measured behaviorally. In addition to taking medications, continuing participation in exercise programs and using self-management techniques such as biofeedback, cognitive behavioral therapy and other individualized physical and psychological practices are essential elements for successful chronic pain management.

Control of chronic non-malignant pain is expected to involve the use of medication. Strategies for pharmacological control of pain cannot be precisely specified in advance. Rather, drug treatment requires close monitoring of the patient’s response to therapy, flexibility on the part of the prescriber and a willingness to change treatment when circumstances change. Many of the drugs discussed in the medication section were licensed for indications other than analgesia, but are effective in the control of some types of chronic pain.

It is generally wise to begin management with lower cost medications whose efficacy equals higher cost medications and medications with a greater safety profile. Decisions to progress to more expensive, non-generic, and/or riskier products are made based on the drug profile, patient feedback, and improvement in function (WHO [World Health Organization] (n.d.); Ehrlich 2003; Chou 2007). The provider must carefully balance the untoward side effects of the different drugs with therapeutic benefits, as well as monitoring for any drug interactions.

Consensus regarding the use of opioids has generally been reached in the field of cancer pain, where nociceptive mechanisms are usually identifiable, expected survival may be short, and symptomatic relief is emphasized more than functional outcomes. In injured workers, by contrast, central and neuropathic mechanisms frequently overshadow nociceptive processes, expected survival is relatively long, and return to a high level of function is a major goal of treatment. Approaches to pain, which were developed in the context of malignant pain, therefore may not be transferable to chronic non-malignant pain.

All medications should be given an appropriate trial in order to test for therapeutic effect. The length of an appropriate trial varies widely depending on the individual drug. Certain medications may take several months to determine the efficacy, while others require only a few doses. It is recommended that patients with chronic nonmalignant pain be maintained on drugs that have the least serious side effects. For example, patients need to be tried or continued on acetaminophen and/or low dose generic antidepressant medications whenever feasible, as part of their overall treatment for chronic pain. Patients with renal or hepatic disease may need increased dosing intervals with chronic acetaminophen use. Chronic use of NSAIDs is generally not recommended due to increased risk of cardiovascular events and GI bleeding. There is good evidence that naproxen has the least risk for cardiovascular events when compared to other NSAIDs (Trelle S 2011). There is good evidence that glucosamine does not improve pain related disability in those with chronic low back pain and degenerative changes on radiologic studies; therefore, it is not recommended for chronic spinal or non-joint pain (Wilkens P 2010). For chronic pain related to joint osteoarthritis see specific extremity guidelines.

Opioid analgesics and other drugs of potential abuse such as sedative hypnotics or benzodiazepines may be used in properly selected cases (Gourlay D 2009) for chronic pain patients, although total elimination of these medications is desirable whenever clinically feasible. It is strongly recommended that such pharmacological management be monitored or managed by an experienced pain medicine physician. Multimodal therapy is the preferred mode of treatment for chronic pain patients whether or not these drugs were used acutely or sub-acutely.

Neuropathic pain can be treated with a variety of medications; however, all have specific side effects and other interactions that clinicians must be mindful of. It is suggested that patients with significant peripheral neuropathic pain be trialed with a tricyclic medication initially, as low dose medication in this category is frequently tolerated and performs sufficiently to decrease pain 30 to 50% (Wiffen PJ, McQuay, Edwards, [Cochrane] 2005). When these fail, side effects are not tolerated, or a patient has medical issues precluding the use of this class of drugs, other appropriate medications can be tried. Second line drugs include the anti-convulsants, gabapentin and pregabalin. Comparison studies of amitriptyline (Elavil, Endep, Vanatrip) and gabapentin (Fanatrex, Gabarone, Gralise, Horizant, Neurontin) or carbamazepine (Carbatrol, Epitol, Equetro, Tegretol) have shown no appreciable difference between the drugs; thus, there is good evidence that there is little clinical outcome difference between the medications although gabapentin may be better tolerated (Saarto T [Cochrane] 2007; Rowbotham, 2004; Rintala D 2007). Third line drugs are the SNRIs, which have demonstrated some effectiveness for treating neuropathic pain, and topical lidocaine (Moulin DE 2007; O’Connor A 2009). The SNRI duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela) has not been shown to be superior to the tricyclic amitriptyline (Kaur 2011) and there is no reason to prefer duloxetine in patients who have not been treated with a tricyclic. Fourth line drugs are opioids, tramadol (Rybix, Ryzolt, Ultram), and tapentadol (Nucynta). Other medications have few clinical trials to support them but may be helpful in some patients.

The preceding principles do not apply to chronic headache patients. These patients should be referred to a physician specializing in the diagnosis and treatment of headache and facial pain (DOWC, [Traumatic Brain Injury MTG], 2006).

For the clinician to interpret the following material, it should be noted that: (1) drug profiles listed are not complete; (2) dosing of drugs will depend upon the specific drug, especially for off-label use; and (3) not all drugs within each class are listed, and other drugs within the class may be appropriate for individual cases. Clinicians should refer to informational texts or consult a pharmacist before prescribing unfamiliar medications or when there is a concern for drug interactions.

The following drug classes are listed in alphabetical order, not in order of suggested use which is outlined above for neuropathic pain.

Alpha-Acting Agents: Noradrenergic pain-modulating systems are present in the central nervous system and the alpha-2 adrenergic receptor may be involved in the functioning of these pathways. Alpha-2 agonists may act by stimulating receptors in the substantia gelatinosa of the dorsal horn of the spinal cord, inhibiting the transmission of nociceptive signals. Spasticity may be reduced by presynaptic inhibition of motor neurons. Given limited experience with their use, they cannot be considered first-line or second line analgesics for neurogenic pain, but a trial of their use may be warranted in some cases of refractory pain.

Clonidine (Catapres, Kapvay, Nexiclon)

Description – central alpha 2 agonist.

Indications – sympathetically mediated pain, treatment of withdrawal from opioids. IV clonidine and lidocaine should be used for upper extremity surgery with IV regional anesthesia in patients with a history of CRPS as there is some evidence that it decreases the risk of recurrence (Reuben, 2004).

As of the time of this guideline writing, formulations of clonidine have been FDA approved for hypertension.

Major Contraindications – severe coronary insufficiency, renal impairment.

Dosing and Time to Therapeutic Effect – increase dosage weekly to therapeutic effect.

Major Side Effects – sedation, hypotension, sexual dysfunction, thrombocytopenia, weight gain, agitation, rebound hypertension with cessation.

Drug Interactions – beta adrenergics, tricyclic antidepressants.

Laboratory Monitoring – Renal function, blood pressure.

Anticonvulsants: Although the mechanism of action of anticonvulsant drugs in neuropathic pain states remains to be fully defined, some appear to act as nonselective sodium channel blocking agents. A large variety of sodium channels are present in nervous tissue, and some of these are important mediators of nociception, as they are found primarily in unmyelinated fibers and their density increases following nerve injury. While the pharmacodynamic effects of the various anticonvulsant drugs are similar, the pharmacokinetic effects differ significantly. Gabapentin and pre-gabapentin, by contrast, is a relatively non-significant enzyme inducer, creating fewer drug interactions. Because anticonvulsant drugs may have more problematic side-effect profiles, their use should usually be deferred until tricyclic-related medications have failed to relieve pain. All patients on these medications should be monitored for suicidal ideation.

Carbamazepine has important effects as an inducer of hepatic enzymes and may influence the metabolism of other drugs enough to present problems in patients taking interacting drugs. There is some evidence that oxcarbazepine (Trileptal) may be effective for neuropathic pain (Dogra, 2005) but dose escalation must be done carefully, since there is good evidence (Dogra, 2005; Beydoun, 2006) that rapid dose titration produces side-effects greater than the analgesic benefits. Carbamazepine is generally not recommended (Moulin, 2007).

There is an association between older anticonvulsants including gabapentin and non-traumatic fractures for patients older than 50; this should be taken into account when prescribing these medications (Jette N 2011).

Gabapentin (Fanatrex, Gabarone, Gralise, Horizant, Neurontin)

Description – Structurally related to gamma-aminobutyric acid (GABA) but does not interact with GABA receptors.

Indications – As of the time of this guideline writing formulations of gabapentin has been FDA approved for post-herpetic neuralgia and partial seizures.

There is some evidence that gabapentin may benefit some patients with post-traumatic neuropathic pain (Gordh T 2008). There is good evidence that gabapentin is not superior to amitriptyline (Rintala D 2007; Saarto T [Cochrane] 2007). There is some evidence that nortriptyline (Aventyl, Pamelor) and gabapentin are equally effective for pain relief of post herpetic neuralgia (Chandra K 2006). There is some evidence that gabapentin given with morphine may result in lower side effects from morphine and produces greater analgesia at lower doses than those usually required for either medication alone (Gilron I 2005). There is strong evidence that gabapentin is more effective than placebo for neuropathic pain, even though it provides complete pain relief to a minority of patients (Wiffen, Derry, 2005; Irving, 2009). There is some evidence that a combination of gabapentin and nortriptyline provides more effective pain relief than monotherapy with either drug (Gilron 2009). Given the cost of gabapentin it is recommended that patients who are medically appropriate receive a trial of tricyclics before use of gabapentin.

Relative Contraindications – Renal insufficiency. Dosage may be adjusted to accommodate renal dysfunction.

Dosing and Time to Therapeutic Effect – Dosage should be initiated at a low dose in order to avoid somnolence and may require 4 to 8 weeks for titration. Dosage should be adjusted individually.

Major Side Effects – Sedation, confusion, dizziness, peripheral edema. Patients should also be monitored for suicidal ideation and drug abuse.

Drug Interactions – antacids.

Laboratory Monitoring – Renal function.

Pregabalin (Lyrica)

Description – Structurally related to gamma-aminobutyric acid (GABA) but does not interact with GABA receptors.

Indications –As of the time of this guideline writing formulations of pregabalin have been FDA approved for neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, and fibromyalgia. It may also be an adjunctive therapy for partial-onset seizures.

There is strong evidence that pregabalin has a substantive benefit for a minority, about 25%, of neuropathic pain patients, most of whom report between 30 and 50% relief of symptoms (Van Seventer R 2010; Moore RA [Cochrane] 2009). Given the cost of pregabalin and its response for a minority of patients it is recommended that patients who are medically appropriate receive a trial of amitriptyline or another first-line agent before use of pregabalin.

Contraindications – allergy to medication, prior history of angioedema. Renal insufficiency is a relative contraindication, requiring a modified dose.

Dosing and Time to Therapeutic Effect – Dosage may be increased over several days and doses above 150 mg are usually required. The full benefit may not be achieved for 6 to 8 weeks.

Major Side Effects – Dizziness, confusion, sedation, dry mouth, weight gain, and visual changes have been reported. Patients should also be monitored for suicidal ideation and drug abuse. Congestive heart failure may be exacerbated in some patients. Decreased platelets have been reported.

Drug Interactions – Opioids, benzodiazepines, and alcohol.

Laboratory Monitoring – Renal function, and platelets, and creatinine kinase as appropriate for individual cases.

Topiramate (Topamax, Topiragen)

Description – Sulfamate substitute monosacchride.

Indications – FDA approved for partial seizures or prophylaxis for migraines. There is good evidence that topiramate demonstrates minimal effect on chronic lumbar radiculopathy or other neuropathic pain (Thienel U 2004; Raskin P 2004; Khoromi S 2005). . Therefore it is generally not recommended for chronic pain with the exception of chronic, functionally impairing headache. If it is utilized this would be done as a third or fourth line medication in appropriate patients.

Lamotrigine (Lamictal) – This anti-convulsant drug is not FDA approved for use with neuropathic pain. Due to reported deaths from toxic epidermal necrolysis and Stevens Johnson syndrome, increased suicide risk, and incidents of aseptic meningitis, it is used with caution for patients with seizure or mood disorders. There is good evidence that lamotrigine is not effective for neuropathic pain and that the potential harms are likely to outweigh the benefits, therefore it is not recommended for most patients (Wiffen, 2007 [Cochrane]; Vinik A 2007).

Antidepressants: are classified into a number of categories based on their chemical structure and their effects on neurotransmitter systems. Their effects on depression are attributed to their actions on disposition of norepinephrine and serotonin at the level of the synapse; although these synaptic actions are immediate, the symptomatic response in depression is delayed by several weeks. When used for chronic pain, the effects may in part arise from treatment of underlying depression, but may also involve additional neuromodulatory effects on endogenous opioid systems, raising pain thresholds at the level of the spinal cord.

Pain responses may occur at lower drug doses with shorter times to symptomatic response than are observed when the same compounds are used in the treatment of mood disorders. Neuropathic pain, diabetic neuropathy, post-herpetic neuralgia, and cancer-related pain may respond to antidepressant doses low enough to avoid adverse effects that often complicate the treatment of depression. First line drugs for neuropathic pain are the tricyclics with the newer formulations having better side effect profiles. SNRIs are considered second line drugs due to their costs and the number needed to treat for a response. SSRIs are used generally for depression rather than neuropathic pain and should not be combined with moderate to high-dose tricyclics (Moulin DE 2007).

All patients being considered for anti-depressant therapy should be evaluated and continually monitored for suicidal ideation and mood swings.

Tricyclics and older agents.

(e.g., amitriptyline, nortriptyline, doxepin (Adapin, Silenor, Sinequan), desipramine (Norpramin, Pertofrane), imipramine (Tofranil), trazodone Desyrel, Oleptro)).

Description – Serotonergics, typically tricyclic antidepressants (TCAs), are utilized for their serotonergic properties as increasing CNS serotonergic tone can help decrease pain perception in non-antidepressant dosages. Amitriptyline is known for its ability to repair Stage 4 sleep architecture, a frequent problem found in chronic pain patients and to treat depression, frequently associated with chronic pain. However, higher doses may produce more cholinergic side effects than newer tricyclics such as nortriptyline and desipramine. Doxepin and trimipramine also have sedative effects.

Indications – Some formulations are FDA approved for depression and anxiety. For the purposes of this guideline, they are recommended for neuropathic pain and insomnia. They are not recommended as a drug treatment for depression. There is good evidence that gabapentin is not superior to amitriptyline (Rintala D 2007; Saarto T [Cochrane] 2007). Given the cost of gabapentin it is recommended that patients who are medically appropriate to undergo a trial of lower cost tricyclic before use of gabapentin.

Major Contraindications – Cardiac disease or dysrhythmia, glaucoma, prostatic hypertrophy, seizures, high suicide risk, uncontrolled hypertension and orthostatic hypotension. A screening cardiogram may be done for those 40 or older (O’Connor A 2009), especially if higher doses are used.

Dosing and Time to Therapeutic Effect – Varies by specific tricyclic. Low dosages, less than 100 mg are commonly used for chronic pain and/or insomnia. Lower doses decrease side effects and cardiovascular risks.

Major Side Effects – Side effects vary according to the medication used; however, the side effect profile for all of these medications is generally higher in all areas except GI distress, which is more common among the SSRIs and SNRIs. Anticholinergic side effects include, but not limited to, dry mouth, sedation, orthostatic hypotension, cardiac arrhythmia, urinary retention, and weight gain. Patients should also be monitored for suicidal ideation and drug abuse.

Drug Interactions – Tramadol (may cause seizures, both also increase serotonin/norepinephrine, so serotonin syndrome is a concern), clonidine, cimetidine (Tagemet), sympathomimetics, valproic acid (Depakene, Depakote, Epilim, Stavzor), warfarin (Coumadin, Jantoven, Marfarin), carbamazepine, bupropion (Aplezin, Budeprion, Buproban, Forfivo, Wellbutrin, Zyban), anticholinergics, quinolones.

Recommended Laboratory Monitoring – Renal and hepatic function. EKG for those on high dosages, or with cardiac risk.

Selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram (Celexa), fluoxetine (Prozac, Rapiflux, Sarafem, Selfemra), paroxetine (Paxil, Pexeva), sertraline (Zoloft)) are not recommended for neuropathic pain. They may be used for depression.

Selective Serotonin Nor-epinephrine Reuptake Inhibitor (SSNRI)/Serotonin Nor-epinephrine Reuptake Inhibitors (SNRI).

Description – Venlafaxine (Effexor), duloxetine, and milnacipran (Savella).

Indications – At the time of this guideline writing, duloxetine has been FDA approved for treatment of diabetic neuropathic pain and chronic musculoskeletal pain. There is good evidence that it is superior to placebo for neuropathic pain at doses of 60mg or 120mg (Lunn M [Cochrane] 2009; Goldstein D 2005). There is some evidence that it is comparable to pregabalin and gabapentin (Quilici, 2009).

As of the time of this guideline writing, formulations of venlafaxine hydrochloride has been FDA approved for generalized anxiety disorder. There is some evidence it is modestly effective in diabetic neuropathic pain at doses of 150 to 225 mg (Rowbotham MC 2004). There is no evidence of superiority over tricyclics.

As of the time of this guideline writing formulations of milnacipran have been FDA approved for treatment of fibromyalgia and has a success rate similar to imipramine. It is not recommended in patients as a first or second line treatment and is reserved for patients who fail other regimes due to side effects.

Relative Contraindications – Seizures, eating disorders.

Major Side Effects - Depends on the drug, but commonly includes dry mouth, nausea, fatigue, constipation, and abnormal bleeding. Serotonin syndrome is also a risk. GI distress, drowsiness, sexual dysfunction less than other classes. Hypertension and glaucoma (venlafaxine). Cardiac issues with venlafaxine and withdrawal symptoms unless tapered (O’Connor A 2009). Studies show increased suicidal ideation and attempts in adolescents and young adults. Patients should also be monitored for suicidal ideation and drug abuse.

Drug Interactions – Drug specific.

Laboratory Monitoring – Drug specific. Hepatic and renal monitoring, venlafaxine may cause cholesterol or triglyceride increases.

Atypical Antidepressants/Other Agents. May be used for depression; however, are not appropriate for neuropathic pain.

Hypnotics and Sedatives: Sedative and hypnotic drugs decrease activity and induce drowsiness and may cause moderate agitation in some individuals. Many other medications, such as antihistamines and antidepressants also produce these side effects. Due to the addiction potential, withdrawal symptoms, and sedating side effects benzodiazepines and other similar drugs found in this class, are not generally recommended. They should be used with extreme caution when the patient is on chronic opioids management. When used, extensive patient education should be documented. Some of these medications have long half-lives and sleep apnea can occur or be aggravated on these medications. Many unintentional drug deaths are related to concomitant opioid and benzodiazepine drug use. Retrograde amnesia can occur and is implicated in “sleep driving,” “sleep eating” and other activities.

Most insomnia in chronic pain patients should be managed primarily through behavioral interventions, with medications as secondary measures (refer to Section F.4, Disturbances of Sleep).

Zaleplon (Sonata), Eszopiclone (Lunesta, Lunestar), Zolpidem (Ambien, Edluar, Intermezzo, Zolpimist).

Description – A nonbenzodiazepine hypnotic.

Indications – As of the time of this guideline writing, formulations of zaleplon, eszopiclonem and zolpidem have been FDA approved for insomnia.

Dosing and Time to Therapeutic Effect – Time of onset is 30 to 60 minutes.

Major Side Effects – Dizziness, dose-related amnesia.

Drug Interactions – Increases sedative effect of other central nervous system (CNS) depressant drugs.

Laboratory Monitoring