Are There Non-Opioid Alternatives For Nerve Pain?

Today's post from medscape.com (see link below) is an important one because it highlights the dilemmas facing doctors and patients alike when it comes to medicating severe neuropathic pain. The situation at the moment is clear: there is a global (but mainly North American) outcry at the use and abuse of opioid-strength medications and this has triggered a frantic search amongst the scientific community for non-opioid medications that are both strong and effective enough to combat nerve pain at its worst. This article is directed at trainee doctors and nurses and examines the problem in a sensible and well-balanced way and for that reason it's very interesting for neuropathic patients who have no option at the moment but to use the only means available for suppressing their pain and that is the opioid family of medications. It may seem a little technical but it will provide you with so much information about the thinking behind nerve pain drug prescription.

Non-Narcotic Options for Pain Relief with Chronic Neuropathic Conditions
Donna V. Wright, MS, RN, FNP
Journal for Nurse Practitioners. 2008;4(4):263-270.

Neuropathic pain is a misunderstood, usually inadequately treated condition. This article discusses the types of pain, mechanisms of pain, diagnosis, and rationale for treating neuropathic pain. The importance of working with patients to achieve their functioning goals is also addressed.

Tom Jacobson, a bail bondsman, is not getting adequate pain relief from hydrocodone/acetaminophen 10/500 (Lortab) four times a day. He is suffering from chronic low back pain with peripheral neuropathy secondary to a motor vehicle accident. He knows that his back pain is a long-term condition (with chronic pain, the recommended daily dose of acetaminophen is 2000 mg to minimize the risk of liver damage; therefore, increasing his daily doses is not an option). He has tried the generic equivalent with less acetaminophen and with less than satisfactory results. He does not want to take the next step up the pain ladder to oxycodone/acetaminophen (Percocet) at this time. He knows that in South Carolina, by changing his prescription to a schedule II medication, he will be required to obtain a new prescription monthly and that his nurse practitioner can no longer prescribe independently of her physician preceptor (in 29 states, prescription of scheduled drugs requires physician collaboration.)[1] This increase in required medical supervision and possible change of caregiver can be a deterrent for some patients. The most important consideration for Tom is the nature of his work. He does not believe that he can function effectively in his role unless he feels "totally in control." The nature of narcotic medications makes this a concern.

To better understand some of the mechanisms of neuropathic pain, a review of the types of pain, the mechanisms, the diagnosis, and the treatment of neuropathic pain is in order. Cadden describes three types of pain: acute, chronic, and acute on chronic.[2] Tom is experiencing chronic pain, which simplifies his care. When chronic pain sufferers have acute pain as well as chronic pain, they are at risk for undertreatment of pain. Table 1 reviews terms used to describe pain. There are basically three ways to treat pain: alter the central pain perception (inhibit mechanisms of pain perception in the dorsal horn of the spinal cord"'how most narcotics work), modify the pain source, and block transmission of pain impulses by modulating the transmission of the pain impulse.[2] The last mechanism is the area in which we will focus.

"Chronic neuropathic pain is the net result of sensory input greater than the central inhibitory response" the uniqueness of chronic neuropathic pain is that its multiple etiologies share a common pathway."[5] The pain signal is processed via the dorsal horn of the spinal cord and transmitted in the central nervous system (CNS). After an injury, the healing process may be altered and actually increase rather than decrease the pain response. The development of dendritic growth (neuroplasticity) can increase the number of alternate neural pathways, which may actually increase the sensitivity to pain. These alternate pathways may have an accumulation of Na+ channels that become "leaky" and fire spontaneously or with very little provocation. "Neurons fire, or spontaneously produce electrical impulses on a regular basis" they may fire more or less slowly depending on whether or not they are excited or inhibited from firing by various types of chemicals called neurotransmitters" naturally occurring chemicals i.e. substance P, glutamate and aspartate excite neurons responsible for pain transmission" drugs that block the action of these substances diminish our awareness of pain. Our body's narcotic chemicals in the brain and the spinal cord inhibit the transmission of pain impulses."[6] By decreasing the rate of impulse firing, these chemicals can help modulate the pain response. The chemicals or neurotransmitters involved are commonly affected by anticonvulsants, antidepressants, neuroleptics, and antiarrythmics (ie, betabockers, sodium channel blockers, acetycholinesterase inhibitors) ( Table 2 , Table 3 ). This very simplified explanation helps provide rationale for the diagnostic criteria and the management of neuropathic pain.

The initial goals for diagnosis according to Gilron[8] include: rule out treatable conditions (ie, a neoplasm), confirm the diagnosis of neuropathic pain, and identify the clinical features (ie, insomnia) that help individualize treatment. Neuropathic pain is most frequently diagnosed by history and examination. A common presentation would be a level of pain intensity that is disproportionate to the injury received. There may be a history of sensory disturbance (numbness, abnormal sensations, itching, burning, pricking) that worsens as the day progresses. This pain pattern may initially follow a dermatonal distribution but can begin to deviate as neuronal plastic changes advance. The development of new "leaky" neural pathways (neuroplasticity) after an injury can set the stage for development of chronic burning or electric (tingling, shocking, jolting) sensations. These overly sensitive pathways can become "exquisitely painful" or sensitive to sensations that are normally not considered painful (allodynia). Other manifestations of neuropathic pain are dysesthesia, altered or abnormal sensations, paresthesias, or hyperalgias. These pains can occur spontaneously due to regrowth connections to sympathetic nerve fibers or can be evoked. It may become difficult for the sufferer to perform his or her usual daily activities.

It is important to determine which medications or treatments have been attempted. Acetaminophen and nonsteroidal antiinflammatories (NSAIDs) are usually not effective. Concurrent alcohol or substance use and abuse issues can complicate treatment. This delayed symptomology combined with a tendency for the pain path to follow a dermatonal distribution meet the diagnositic criteria for neuropathic pain.[9]

On physical examination, disturbances in light touch, response to pin pricks, vibration, and proprioception may be noted. Sensory disturbances may be beyond the discrete nerve territory. There may be pain with a straight-leg raise exam, which suggests irritation of a lumbar root; Phalen's test or Tinell's sign may be positive (usually indicates carpal tunnel). Deep tendon reflexes may be abnormal. A skin examination may show temperature, color, and hair growth changes, along with abnormal sweating.[8] Stimulus-evoked hypersensitivities may be present and can occur in areas that have loss of sensation. "The symptoms most associated with neuropathic pain were dysesthesias, evoked pain, paroxysmal pain, thermal pain, autonomic complaints, and descriptions of the pain as being sharp, hot or cold, with high sensitivity."[10] It is common for there to be a relatively modest demonstration of clinical neurological deficits or an essentially normal examination.[10]

Confirmatory diagnostics include computed tomography (CT) scans and magnetic resonance images (MRIs) that may show compromised nerve root pathways and structural damage; electromyography and nerve conduction studies, which can show the extent of neuroplastic changes; quantitative sensory testing (QST "' measures sensory thresholds for pain, touch, vibration, and temperature); and three-phase nuclear medicine bone scans that may help diagnose complex regional pain syndrome (CRPS).[10] During the diagnostic phase, a physiatrist (a physician who specializes in physical and rehabilitation medicine) can be an invaluable ally who can perform and interpret many of these examinations as well as suggest other diagnostic tests that might be appropriate.

Once the diagnosis has been confirmed, the practitioner may want to consider using conservative nonpharmacologic treatment options. These options can be crucial if the patient has a history of alcohol and/or substance abuse. Consider the physical conditions and activities that may increase pain. Watch the patient walk, move, and transfer. Large wallets, improper shoes (especially heels and boots), inappropriate canes and walkers, and gaits that favor one leg or another can increase neuropathic pain. Also, evaluate physical activities that may be exacerbating pain. Riding lawnmowers, all-terrain vehicles, and post-hole diggers are among the common culprits.

Physical therapy may be an appropriate referral for gait training; to determine the need for assistive devices; to determine whether use of a TENS (transcutaneous electrical nerve stimulation) unit would be appropriate; to initiate the use of massage, therapeutic exercises, cold, heat, hydrotherapy, electrical stimulation, or light therapy; to improve the general physical condition and reduce stress levels;[9] or to assist with the development of a set of guidelines for patient activity. A physiatrist may not only be able to assist in confirming the diagnosis but also in performing nerve blocks (injection of an anesthetic to "deaden" a specific nerve pathway), facet injections (use of a corticosteroid to decrease inflammation around a nerve root), and in recommending appropriate physiologic therapies.

The other specialists that you may wish to consult include a pain clinic referral[9] (a facility supervised by a physician, usually an anesthesiologist, who specializes in pain management) for nerve blocks and other injections; a chiropractor[9] (a practitioner who uses spinal manipulation to treat disorders of the nervous system); or a homeopath[9] (a practitioner who uses a system of therapeutics based on the theory that "like cures like"). Due to the emotional impact of chronic pain, a referral to a behavioral therapist may be appropriate. This therapist may suggest various therapies to improve the patient's coping level, reduce stress, and raise the pain threshold, which include relaxation, biofeedback, distraction, or attendance at a support group.[9] "Early referrals for nerve blocks and injections can promote the effectiveness of physiotherapy and pain rehabilitation."[8] While you hate to discourage activity with chronic pain, management of pain requires that the patient achieve a balance between activity and rest.

What pharmacologic options are available for the nurse practitioner who wants to help his or her patients maintain their functional levels? "Pharmacologic interventions follow the guidelines of the three-step analgesic ladder for pain control as developed by the World Health Organization (WHO). Step 1: Mild pain is usually treated with aspirin, acetaminophen, or nonsteroidal antiinflammatories (NSAIDs).[11] This is usually not an appropriate treatment level for neuropathic pain. Step 2: "Step 2 of the WHO three-step ladder includes mild opiates" along with the adjuvant medications."[9] In this instance, the nurse practitioner may be delaying or minimizing the use of stronger opiods (i.e. morphine) which are reserved for moderate-to-severe pain (Step 3 of the WHO ladder). This combination can decrease the incidence of side effects and increase the functional level of patients. Which medication is best? Table 4 suggests options. However, the bottom line is "how functional is your patient with this medication?" Current guidance is that for neuropathic pain, "tricyclic antidepressants are the initial drugs of choice" .amitryptyline, nortriptyline, imipramine, or desipramine." "Second line medications are anticonvulsants that include phenytoin, carbamazepine, and valproic acid" . (they) are especially helpful in cases of neuralgia and paresthesia."[15] Atypical anticonvulsants have had a role in neuropathic pain treatment, ie, gabapentin (Neurontin). The Food and Drug Administration (FDA) also has recommendations based on research.

Antidepressants should be used with caution in patients whose psychiatric history is unknown. A patient with an undiagnosed bipolar disorder can be placed in a hypomanic state or in a state of rapid cycling subsequent to initiation of an antidepressant.[15] Tricyclic antidepressants, ie, amitriptyline (Elavil) have been used as an adjunctive in treatment of neurogenic pain. They are believed to inhibit reuptake of serotonin and norepinephrine. Amitriptyline has multiple drug effects and antiarrythmic effects. Dosing this medication at bedtime can help reduce the impact of sedation. It is a pregnancy category D.[15] It is investigational for adjunctive analgesia with phantom limb pain, migraine, diabetic peripheral neuropathy, peripheral neuropathy pain, and post herpetic neuralgia.[14] Doxepin (Sinequan) works similarly to amitriptyline but with more sedation. Its pregnancy category is NR.[15] Nortriptyline can be used for chronic severe neurogenic pain.[14] Desipramine is investigational for severe neuropathic pain.[14] Imipramine has been used for severe neuropathic pain but has a seizure risk with high therapeutic dosages.[14]

Other antidepressants used for pain control include venlafaxine (Effexor), which potentiates neurotransmitter activity in the CNS, especially serotonin and norepinephrine with weak potentiation of dopamine. This medication should not be discontinued abruptly. It is a pregnancy category C.[15] Duloxetine (Cymbalta) works similarly to venlafaxine. It was the first medication to have FDA approval for diabetic peripheral neuropathy. With duloxetine, you must use caution with severe renal and hepatic disease. It is a pregnancy category C (Lilly insert). With any medication that increases serotonin levels, be aware of the risk of serotonin syndrome. This is especially true when "triptans" (medications used to prevent migraines) and SSRIs (selective serotonin reuptake inhibitors) are used together.[13]

Anticonvulsants have been considered second line for neuropathic pain. One of the most commonly used drugs is gabapentin (Neurontin). It is believed to be a competitive and reversible inhibitor of acetycholinesterase, which decreases the available acetycholine for nerve impulse transmission. The dosage needs to be reduced if the patient has altered renal function. It is a pregnancy category C.[15] It is considered an investigation drug for neuropathic pain and prevention of migraines. It has been approved for treatment of post herpetic neuralgia (PHN). It can be dosed up to 1800 mg/day in three divided doses.[14] Pregabalin (Lyrica) has obtained FDA indications for post herpetic neuralgia, diabetic peripheral neuropathy, and primary fibromyalgia syndrome. It is believed to be a GABA analog that reduces calcium dependent release of several neurotransmitters. The dosing for pregabalin is more linear than that of gabapentin (Pfizer insert).[13]

Another anticonvulsant, carbamazepine (Tegretol) is commonly used for trigeminal neuralgia and restless leg syndrome. It reduces the post tetanic potentiation of synaptic transmissions (it possibly depresses activity in the nucleus ventralis anterior of thalamus, thus decreasing polysynaptic responses).[14] This medication is well known for its multiple drug interactions, especially with warfarin, tricyclic antidepressants, and monamine oxidase inhibitors. It is a pregnancy category D.[15] Valproic acid (Depakene) acts by increasing levels of GABA, an inhibitory transmitter. It may also improve membrane stability by affecting the potassium channel. It has been used for prophylaxis of migraine headache.[14] Concerns include decreased hepatic function, multiple drug interactions, and that it is pregnancy category D.[15] Phenytoin (Dilantin) has also been indicated for neuretic pain"'migraine, trigeminial neuralgia, Bell's palsy. This medication acts by stabilizing neuronal membranes by decreasing the influx of sodium ions across the cell membranes in the motor cortex during generation of nerve impulses. Concerns include hydantoin hypersensitivity, slowed cardiac conduction, and hepatic dysfunction. This medication is also a pregnancy category D.[15] It is considered investigational for trigeminal neuralgia.[14] In theory, any anticonvulsant could be used as an adjuvant. However, be wary of medications not commonly used for pain control. In my practice, the drug Gabitril (tiagabine) has precipitated seizures in nonepileptic patients and should not be used "off label." In fact, an FDA alert was issued February 28, 2005 discouraging off-label use of this medication due to seizure risk in nonepileptics.[13]

Other medications that can be used include skeletal muscle relaxants, ie, lioresal (Baclofen), which has a twofold effect. It inhibits transmission of monosynaptic and polysynaptic reflexes and it causes muscle relaxation. It has indications for analgesia and trigeminal neuralgia. This medication should not be withdrawn abruptly.[15] Its function is related to GABA with CNS depressant effects. It is investigational for trigeminal neuralgia, prevention of migraines, and neuropathic pain.[14] Chloroxazone (Parafon forte) modifies the central perception of pain through its sedative effects. Possible side effects can include angioedema and anaphylaxis.[15]

Do not overlook topical analgesics. In fact, some authors suggest that topical lidocaine should be the first pharmacologic intervention.[8] The three classes most commonly used include[5]:

Local anesthetics "' lidocaine and mexiletine (Mexitil) interfere with the exchange of sodium in the sodium channel. (Some patients find Biofreeze effective at decreasing pain.)

Formulations containing antiinflammatories

Topical capsaicin "' depletes substance p and decreasing transmission of pain impulses.

Consider having a compounding pharmacist tailor topical medications. Consult with the pharmacist regarding the specific compounds and their concentration. Table 5 provides a reference for discussion. Topicals are ideal when patients desire decreased side effects and decreased liver involvement.

Another consideration when choosing an adjuvant is the associated conditions that interfere with pain management. Has the patient recently started on a "statin" for lowering cholesterol levels? Does the patient also suffer from arthritis, muscle spasms, restless leg syndrome, insomnia, diabetes mellitus, or depression? Sometimes treating other conditions allows medications for chronic pain syndromes to work more effectively. Comorbidities may point to appropriate adjuvants. Tricyclic antidepressants are helpful if insomnia is a concern. Baclofen has been known to help with neuropathic pain due to its neurotransmitter and CNS effects. "Steroids have been and continue to be administered by multiple routes for complex regional pain syndrome therapy."[12] Methylprednisolone (Medrol dose pak) is an antiinflammatory and immunosuppressant that can provide significant relief when inflammation is present. It is not for long-term use.[15] "Nonsteroidal anti-inflammatory drugs, physical therapy, accupuncture, antidepressants, and antiepileptics have been used as adjunctive treatment for chronic low back pain."[12] Clonidine (Catapress) stimulates the alpha andrenergic receptors in the CNS, which inhibits the sympathetic vasomotor center and decreases nerve impulse transmission, thus decreasing pain. Side effects include bradycardia and hypotension. This medication has been used for post herpetic neuralgia and restless leg syndrome.

"Pain management requires ongoing evaluation, patient education and reassurance. Diagnostic evaluation of treatable underlying conditions (eg, spinal cord compression, herniated disc, neoplasm) should occur concurrently with pain management."[8] For many patients with neuropathic pain, the nurse practitioner who has developed a comprehensive plan of care and has a strong network for referrals can be the most appropriate primary care provider. However, severe intractable pain may require referral to a pain clinic or neurosurgeon (if significant damage is identified during diagnostic studies). In most cases, "treatments with the lowest risk of adverse effects should be tried first."[8]

There is both an art and a science to pain management. Rowbotham states that the "Treatment of complex regional pain syndrome is largely empirical."[12] Sometimes trial and error is the best guide with any neuropathic pain. Both the practitioner and the patient need a willingness to try various options. If "pain is whatever the person experiencing the pain says it is, existing whenever the patient says it does,"[17] perhaps optimal functioning can be defined similarly. Can optimal functioning be defined as being achieved when the patient can satisfactorily perform at their chosen activity level? My bail bondsman, Tom, is a case in point. After multiple trials, he started using pregabalin as an adjuvant. His pain was more controlled, he felt as if he was "in control," and he became better able to function without excessive sedation. An unqualified success. 

There is both an art and a science to pain management. Rowbotham states that the "Treatment of complex regional pain syndrome is largely empirical."[12] Sometimes trial and error is the best guide with any neuropathic pain. Both the practitioner and the patient need a willingness to try various options. If "pain is whatever the person experiencing the pain says it is, existing whenever the patient says it does,"[17] perhaps optimal functioning can be defined similarly. Can optimal functioning be defined as being achieved when the patient can satisfactorily perform at their chosen activity level? My bail bondsman, Tom, is a case in point. After multiple trials, he started using pregabalin as an adjuvant. His pain was more controlled, he felt as if he was "in control," and he became better able to function without excessive sedation. An unqualified success. 

References (click to open)
Journal for Nurse Practitioners. 2008;4(4):263-270. © 2008 Elsevier Science, Inc.

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