Evidence-Based Treatment of Diabetic Peripheral Neuropathy

Article Outline

• ABSTRACT
• INTRODUCTION AND PATHOPHYSIOLOGY OF PAIN
• PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY
• TREATMENT OF DPN
• FIRST-LINE MEDICATIONS
• SECOND-LINE MEDICATIONS
• OTHER MEDICATIONS
• CASE STUDY
• CONCLUSION
• References
• Copyright

ABSTRACT 

Patients with chronic pain and especially those with diabetic peripheral neuropathy (DPN) are difficult to manage because of their range of pain symptoms and their need for higher levels of pain medication. Enhancing a solid knowledge base for the various causes of nerve damage leading to nerve pain can help the advanced practice nurse to choose effective therapeutic options. With so many medications to treat a wide variety of symptoms, it can be hard for nurse practitioners (NPs) to prescribe the best medication. By dividing the medications into tiers based on efficacy, NPs will be able to effectively treat DPN. Effectively treating patients' pain will optimize health care resources.

Keywords:  Pain , diabetic peripheral neuropathy (DPN) , pain management

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INTRODUCTION AND PATHOPHYSIOLOGY OF PAIN 

Pain as a subjective experience takes on many characteristics. It is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”¹ Two major groups of pain characteristics are recognized: nociceptive and neuropathic. Nociceptive pain is finite, localized, and subsides after the stimuli is no longer present. Thus, by removing the stimulus, pain is relieved. Neuropathic pain is the result of a lesion or dysfunction in the nervous system, nerve damage, or a change within the pathways that results in chronic pain in the absence of a stimulus.² Chronic pain is pain without apparent biological value that has persisted beyond normal tissue healing time or about 3 months.³

Neuropathic pain symptoms have since been divided into positive and negative sensory symptoms. Positive symptoms refer to an increased type of sensation and include pain, paresthesia, dysesthesia, and hyperalgesia. Negative symptoms refer to a loss of sensation and include hypoesthesia and hypoalgesia.⁴

Normally, nociceptors are triggered by endogenous and exogenous stimuli. This signal is then transmitted through A-delta fibers and C-delta fibers. A-delta fibers are myelinated, allowing a fast transmission, and these sensations are often sharp or pricking. C-delta fibers are unmyelinated, producing a slower transmission, and are associated with dull or burning sensations. A- and C-delta fibers are primarily afferent fibers and connect to the gray matter of the spinal cord in the dorsolateral horn. Here the signal is spread out among many different locations and results in the release of neurotransmitters such as amino glutamate and substance P.⁵

Three main pathways send the signal up the spinal cord to the brain and include the spinothalamic tract, the spinomesencephalic tract, and the spinoreticular tract. The thalamus receives the information from the spinothalamic tract directly and receives collateral information from the other tracts. The thalamus codes the information by type, temporal pattern intensity, and localization of the pain. Once coded, the information is sent to the limbic structures and cortical sites. On reaching the cerebral cortex, the information is cognitively and emotionally interpreted. This interpretation involves the insular cortex, anterior cingulated cortex, and medial prefrontal cortex. The sensory-discrimination portion of interpretation includes the intensity, location, duration, temporal pattern, and quality. The motivational-affective portion describes the relationship between the pain and mood, attention, coping, tolerance, and rational reaction.⁵

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PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY 

Diabetic peripheral neuropathy (DPN) is a form of chronic neuropathic pain. The pain stimulus is endogenous and is related to the effects of hyperglycemia on the nerve and vasculature. Several theories explain the specific initiation of the pain stimulus, but the exact cause is still unknown. Excess glucose is shunted through the polyol pathway. This pathway reduces glucose to sorbitol by aldose reductase and oxidizes NADPH (nicotinamide-adenine dinucleotide phosphate) to NADP⁺ (oxidized nicotinamide-adenine dinucleotide phosphate). Sorbitol is then oxidized to fructose by sorbitol dehydrogenase and reduces NAD⁺ (reduced nicotinamide-adenine dinucleotide) to NADH (reduced nicotinamide-adenine dinucleotide). This series of reactions results in many chemical changes that affect the body and are summarized in Box 1. These changes cause an oxidative stress and may result in vasoconstriction.⁶

In diabetes abnormal carnitine metabolism causes slowed nerve conduction and increased vascular permeability. Carnitine along with short-chain esters facilitate the transport of long-chain fatty acids across the inner mitochondrial membrane for oxidation that results in available energy. In diabetes, the long-chain fatty acids accumulate to toxic levels from the abnormal carnitine metabolism.⁶

Hyperglycemia also affects the neuronal cells by altering numerous cellular functions. Hyperglycemia may cause parenchyma damage from alterations in activity of key axonal enzymes such as sodium-potassium (NaK) and adenosine triphosphatase (ATP) along with a reduction in levels of neurotrophic factors. This results in neuronal loss from activation of apoptosis. Through magnetic resonance imaging studies, endoneurial edema has been noted, which contributes to increased endoneurial pressure and capillary narrowing with resultant nerve ischemia.⁷

Thickening of axons may be related to increased axonal intracellular fluid early in the course of diabetes. This along with a decrease in microfilaments and capillary narrowing of the small myelinated and demyelinated C fibers can result in loss of axons. Impaired nerve blood flow can also result from a reduction in the endothelial-dependent and nitric oxide–dependent vasorelaxation in the endoneurium. There may also be an increased expression or action of vasoconstrictors such as endothelin 1.⁷

A RAGE (receptor for advanced glycation end products)–ligand interaction may play a role in neuronal dysfunction. AGE (advanced glycation end products) formation occurs from an overproduction of mitochondrial superoxide from hyperglycemia. This causes an increased blood-nerve barrier permeability, causing vascular and neuronal dysfunction.⁸ These changes include an interference with cellular adhesion and interaction and altered protein transport and function⁹ (Box 2).

Regardless of the cause of nerve or vascular insult, patients initially present with positive pain symptoms, and, as the disease progresses, they experience negative pain symptoms.⁷ Often the neuropathy presents in a “glove-stocking” appearance that affects the legs more than the arms. The nerves are “dying back” in a distal to proximal fashion from failure of the neuron, ischemic effects of vascular abnormalities, or deleterious effects of glycation on the Schwann cells or extracellular matrix.⁹

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TREATMENT OF DPN 

Neuropathic pain medications are classified into three groups, as suggested by evidenced-based research, ranging from most efficacious to least. These groups include first-line, second-line, and other medications. First-line medications are generally more thoroughly researched and can be used as the sole agent for treatment. These medications include gabapentin, the 5% lidocaine patch, opioids, tramadol, and tricyclic antidepressants (TCAs). Refer to Table 1 for a quick reference guide.

Table 1. First-Line Medications

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FIRST-LINE MEDICATIONS 

Gabapentin (Neurontin) is a calcium-channel blocker that is renally excreted. Damaged or demyelinated nerves spontaneously fire, have excess voltage, and have extra-sensitive electrolyte channels in the affected area. Gabapentin works by modifying the spinal transmission of these noxious mechanical inputs. It also binds to the calcium channels and works to inhibit the release of excitatory neurotransmitters. The antihyperalgesia and antiallodynia effects are related to the stabilization of the dorsal horn neurons.¹⁰

Gabapentin has been found to be effective in treating postherpetic neuralgia, DPN, phantom limb pain, Guillain-Barré, and other mixed neuropathies. The target dose is 1800 to 3600 mg/day.¹¹ The drug peaks in 1 to 3 hours with a half-life of 5 to 7 hours.¹²

Gabapentin needs to be titrated in increments of 100 to 300 mg every 1 to 7 days. Titration continues until adequate pain relief is achieved or unacceptable side effects occur. Titration up to the target dose should take 3 to 8 weeks with 1 to 2 weeks at the target dose for a maximum trial effect. A slow titration allows for a tolerance to the side effects. The most common side effects include drowsiness, gastrointestinal disturbance, and cognitive impairment in the elderly.¹¹ Patients need to be monitored for dizziness and peripheral edema.¹³

For DPN, effective gabapentin levels are 900 to 3600 mg/day, and at these doses patients had decreased pain, increased sleep, and improved quality of life.⁴ Gabapentin is not effective in treating acute pain or pain with no objective nerve injury. Patients should not drive until mental or motor depression has been ruled out. If used along with morphine, gabapentin concentrations and central nervous system (CNS) depression may increase as a result of synergistic effects.¹³

The 5% lidocaine patch works as an analgesic and also serves as a barrier from chaffing clothes.⁴ The patch should be applied directly to the affected area. Apply no more than three patches daily with a schedule of 12 hours on and 12 hours off. Using the patch for 2 weeks is a sufficient trial for pain relief, and there is no need to use titration. With normal hepatic function, blood levels of the drug are minimal. It is currently approved by the Food and Drug Administration (FDA) for postherpetic neuralgia and allodynia. Side effects include a mild skin reaction, and it must be used with caution for patients taking class 1 antiarrhythmic drugs (eg, mexiletine, quinidine, or procainamide).¹¹ Because the patch is not sterile, it should not be used on open lesions.² Clinical trials for patients with DPN have shown the need for up to four patches to cover the entire painful site. Patients reported reduced pain and increased quality of life.¹⁴

Opioids are affected by the catechol-O-methyltransferase (COMT) gene. This gene produces enzymes at low, medium, or high speeds that metabolize norepinephrine and dopamine. At high enzyme production, more norepinephrine and dopamine are metabolized, and, as a result, a greater number of opioid receptors are activated to relieve pain. Thus, the more active opioid receptors present, the better the pain control is with opioids. These receptors are found mostly in the thalamus and amygdala.¹⁵ Opioids all help reduce pain and improve sleep, but they do not directly improve physical function and mood.¹¹ Opioids are most likely to work if the patient has used them in the past with success for acute, subacute, nociceptive, neuropathic, or mixed pain symptoms.¹⁶

DPN is best treated with controlled-release oxycodone to a maximum of 120 mg/day.¹¹ Oxycodone is good for allodynia or paroxysmal pain.⁴ Patients with widespread and severe pain benefit from opioids such as propoxyphene (Darvon), hydrocodone bitartrate with acetaminophen (Vicodin, Lortab), oxycodone with acetaminophen (Percocet), morphine, or codeine.¹⁷ For short-acting intermittent pain, morphine, oxycodone, or hydrocodone are good medications. For continuous long-acting pain control, controlled-release morphine or methadone appear to be more effective.¹⁸

Use caution with acetaminophen and drugs combined with acetaminophen because liver toxicity can occur with doses greater than 4 g/day. Many combination medications have acetaminophen in them, and patients can overdose on acetaminophen if they take another acetaminophen product. Because neuropathic pain requires higher doses of pain medication, patients may increase the dose of these combination medications without realizing the acetaminophen dose is lethal. In addition, use caution with cyclobenzaprine (Flexeril) and TCAs (they share the same toxic potential), nonopioids with opioids (acetaminophen with Percocet), and tramadol with a seizure risk or with drugs that precipitate seizures (selective serotonin reuptake inhibitors [SSRIs], TCAs, or other antidepressants).¹⁶

When choosing an opioid dose, start with short-acting opioids for 1 to 2 weeks and then calculate a long-acting dose based on the requirements for short-acting medication. If this is not an option, consider starting the specific opioid at a dose equivalent to 5 to 15 mg morphine. An adequate trial lasts 4 to 6 weeks on a stable long-acting medication. For doses greater than 120 to 180 mg, consider involving a pain specialist. For neuropathic pain, there is no established benefit with doses greater than 180 mg/day.¹¹ If no improvement is seen with titration, the pain may not be opioid responsive. There is no predetermined maximum dose with pure agonist opioids, and the body will naturally develop a tolerance to the dose over time. To improve efficacy of opioids, it may help to rotate among opioids.¹⁸ Remember to treat breakthrough pain and evaluate whether the unrelieved pain is due to end-of-dose failure or whether it is incidental to an unrelated activity. Also, spontaneous pain that is fleeting and difficult to predict is common with neuropathic pain.¹⁹

The main side effects of opioids include constipation, nausea, and sedation. Use caution in older adults with risk of falling because of the sedative effects associated with TCAs. Also do not stop the medication abruptly because of the risk of withdrawal symptoms.¹¹ Absolute contraindications to opioid use include allergy, active diversion of controlled substance, and co-administration of a drug capable of inducing life-limiting drug-to-drug interaction (Table 2). Relative contraindications include acute psychiatric instability, suicide risk, history of intolerance or adverse effects, current substance abuse, cognitive impairment, noncompliance, sleep apnea without the use of constant positive airway pressure, chronic obstructive pulmonary disease, and the elderly.¹⁸

Table 2. Possible Drug Interactions With Drugs Used to Treat DPN Pain

MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor. Adapted from: Cauffield JS. Treatment options in neuropathic pain. US Pharmacist. Available at: http://www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/jun00pain.htm. Accessed February 12, 2006.

Tramadol (Ultram) is a centrally acting analgesic that inhibits both norepinephrine and serotonin reuptake and weakly binds to opioid receptors. In a randomized clinical trial with 45 patients with polyneuropathy, the researchers noted a statistically significant reduction in pain when titrations of 400 mg/day were maintained for 8 weeks.²⁰

Dizziness, nausea, constipation, and orthostatic hypotension are possible side effects experienced particularly when quickly titrated; therefore, the drug should be titrated slowly. Tramadol should be started at 50 mg twice daily and titrated by 50 mg to 100 mg daily in divided doses every 3 to 7 days. Tramadol needs to be evaluated for at least 8 weeks for efficacy. Patients with seizure disorders need to be monitored carefully especially if concomitantly taking other drugs that lower the seizure threshold such as opioids or antidepressants. Adjustment in doses is necessary for the elderly and for patients with renal or hepatic impairment.²⁰

TCAs are first-line therapy for treating fibromyalgia and migraines.¹⁵ The analgesic effect is independent of the antidepressant effect.² Because of the anticholinergic and sedative effects, TCA use is limited, especially in treating DPN. Amitriptyline has more severe side effects because it is a norepinephrine and serotonin blocker, whereas nortriptyline and desipramine block only serotonin and have less severe side effects. Amitriptyline is useful in lancinating or shooting pain.⁴ Imipramine works well for pain, paresthesias, dysesthesias, and numbness.⁴ Clomipramine use is recommended over aspirin for dysesthesia, hyperpathia, and causalgia (Box 3).

The side effect profile of TCAs includes hypotension, tachycardia, tremors, sweating, nausea, dry mouth, urinary retention, and constipation.²¹ Because TCAs interact with hypertension medications and can cause QT prolongation, a baseline electrocardiogram is recommended. Use caution in cardiovascular disease, glaucoma, urinary retention, and autonomic neuropathy. Monitor patients for suicide risk, stroke, tachycardia, myocardial infarction, and overdose. Additionally, in the elderly, watch for cognitive impairment and fall risk. The most commonly used TCAs are nortriptyline and desipramine. Start low with 10 to 25 mg at bedtime and titrate up every 3 to 7 days to a maximum of 75 to 150 mg/day. An adequate trial of the drug takes 6 to 8 weeks with 1 to 2 weeks at the maximum dosage.⁴

For all first-line medications, if only partial relief is achieved, consider adding another first-line medication. However, when patients are receiving multiple medications, it is difficult to know which medication is effective and which is causing an undesirable side effect.¹¹ If the five first-line medications are unsuccessful, only partially relieve the pain, or are not an option for the patient, then move to the second-line medications. These medications include lamotrigine, carbamazepine, pregabalin, and antidepressants. Refer to Table 3 for a quick reference guide.

Table 3. Second-Line Medications

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SECOND-LINE MEDICATIONS 

Lamotrigine acts on the sodium and possibly the calcium channels to stabilize the neuronal membranes. It is excreted by the liver and has a half-life of 25 hours.¹² However, slow careful titration is recommended to avoid a severe rash and Stevens-Johnson syndrome.¹¹ For DPN, recommended dosage is 200 to 400 mg/day.⁴

Carbamazepine is useful in treating DPN at 800 mg/day.¹¹ In patients with DPN, carbamazepine has a membrane-stabilizing effect on injured nerves. It decreases ectopic discharges by acting on voltage-sensitive sodium channels. In pain relief, it is equally effective as the combination of nortriptyline and fluphenazine (antipsychotic).⁴ Also in cases in which gabapentin has failed, carbamazepine can serve as another anticonvulsant option if such treatment is sought.¹¹ Side effects include vertigo, fatigue, and gait disturbance.²¹

Pregabalin (Lyrica) is a CNS-active compound analog of the neurotransmitter gamma-aminobutyric acid (GABA). Pregabalin works as an auxiliary protein associated with voltage-gated calcium channels by binding to the alpha₂-delta subunit. This reduces calcium influx at the nerve terminals and reduces the release of other neurotransmitters such as glutamate, noradrenaline, and substance P. This produces the analgesic, anticonvulsant, and anxiolytic activity. Pregabalin does not convert to GABA or a GABA antagonist and does not alter the uptake or degradation of GABA.²² It can decrease pain and improve sleep within 1 week.²³ It is FDA approved for treatment of DPN.²⁴ Normal doses are 300 mg/day with no titration required. Side effects include dizziness, somnolence, peripheral edema, and weight gain. Patients also noted less stress and anxiety with use.²²

Antidepressants are also another option. Paroxetine, citalopram, bupropion, and venlafaxine can all be used as adjunctive treatment if an antidepressant is necessary. Antidepressants should not be used as sole treatment for pain, but rather they should be added to another antidepressant (TCA) if inadequate relief is obtained. Or, antidepressants can be added if a first or second-line pain medication is ineffective and treatment with an antidepressant is sought.¹¹ Cymbalta is a serotonin and norepinephrine reuptake inhibitor initially used to treat depression. However, it is also FDA approved and effective for the treatment of burning, tingling, and numb sensations in the feet, hands, and legs because of DPN. Side effects include nausea, dry mouth, constipation, diarrhea, dizziness, and hot flashes.²⁵

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OTHER MEDICATIONS 

When the first- and second-line medications are ineffective or not a suitable choice, several other medications can be used on an individual basis. These medications are not first-line treatment for any particular disease, but they may help relieve pain when other treatments have failed.¹¹ Refer to Table 4 for a quick reference guide.

Table 4. Other Medications

Capsaicin is the active ingredient in chili peppers that makes them hot. It stimulates small nerve fibers through a nonselective cation receptor called VR1. This receptor produces an influx of calcium ions that activate calcium-sensitive proteases and axonal degeneration. This leads to a reduced number of epidermal and subepidermal nerve fibers and thus reduced pain sensations.²⁶ DPN has been treated effectively with capsaicin. On topical application, the patient may complain of burning that should diminish with use after 5 to 7 days. However, too high of a concentration of the drug can cause destruction of nerve fibers. The burning side effect has made blinded studies impossible because study subjects can readily tell when they have received the intervention.²⁷ Patients should apply the medication 4 to 5 times a day for 4 weeks. Instruct patients to wash their hands thoroughly after applying the medication to the affected area.² Capsaicin is best used as a last resort for individual patients.¹¹ Resiniferatoxin, like capsaicin, works through the same receptor. Unlike capsaicin, there is no burning side effect. This product is still in phase 2 clinical trials.²⁷

Cannabinoids block pain signals through the cannabinoid receptor. Although many receptors register pain stimuli, cannabinoids work outside the central nervous system to reverse hypersensitivity. Therefore, the adverse effects of the drug are minimal.²⁷ Studies found that pain relief was greatest in persons with a lower beginning pain rating; this suggests a limitation of pain reduction. In doses of 40 to 80 mg, pain relief peaked in 3 hours. Side effects include fatigue, dizziness, dry mouth, and sweating.²⁸

Further treatment options include clonidine, dextromethorphan, and mexiletine. However, these drugs should be used on an individual basis because of the inconclusive evidence of efficacy and lack of research.¹¹

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CASE STUDY 

The following case study illustrates the steps often necessary to control the pain associated with DPN. AD is a 54-year-old woman presenting today for a follow-up visit for diabetes management. She reports her finger sticks at home are in fair control, but she complains of insomnia. She has pain, numbness, and tingling in her feet mostly, but it affects her hands at times. The discomfort is keeping her awake at night, and she is now experiencing daytime drowsiness. She describes the nighttime pain as “hot, burning pain” mostly affecting her feet and sometimes her calves. She takes an occasional Tylenol PM (with Benadryl) with little relief She works part time keeping the books for her husband's business and has missed a lot of work lately because of the pain and sleeplessness.

AD has had type 2 diabetes for more than 15 years. Her diabetes is under fair control with her last glycosylated hemoglobin (HgbA_1C) at 7.2%. Her past medical history includes hypertension, type 2 diabetes, hyperlipidemia, menopause at age 51, and intermittent sciatica-type pain. She has no allergies, does not smoke, and drinks a glass of wine per month. She has no surgical history. She walks every day with her dog for about 1 mile. Her current medications include Lantus 12 U SQ every evening, Glucovance 1.25/250 mg bid, Lipitor 40 mg every evening, Lisinopril 40 mg every AM, ASA 81 mg every AM. AD's vital signs are normal (BP 120/78 mm Hg, P 80, RR 16). Her weight is 174 pounds, height is 5 feet 2 inches with a body mass index of 31.8.

Her physical examination is normal with the exception of decreased sensation in both feet as measured by a microfilament fiber. She has decreased vibratory sense up to the pretibial area bilaterally. Her feet are cool with +2 pulses and no lesions.

This patient's pain is described as classic neuropathic pain with the reference to “burning” and “numbness and tingling” sensations. She is in the initial stages of her pain and a first-line medication is a good place to start. The nurse practitioner (NP) prescribes Neurontin 300 mg per day for 1 day, then increase to 300 mg bid for 1 day, then 300 mg tid for several weeks. The NP tells the patient that this medication is effective for this type of neuropathic pain associated with diabetic neuropathy, but it needs to be started at low doses and increased slowly because of CNS side effects such as drowsiness, dizziness, and fatigue. The NP is hoping that the Neurontin will not only assist with insomnia by diminishing her pain but also by causing mild drowsiness. The NP cautions her not to drive or perform other hazardous activities while she is titrating this medication.

When AD questions the NP about interactions with her other medications, the NP informs AD that Neurontin does not interact adversely with her current medications. The patient is scheduled to return for pain management follow-up in 1 month.

On her return visit 1 month later, AD is sleeping better with the Neurontin at 300 mg tid. She is tolerating it well and plans to continue.

Six months later, the patient is beginning to experience severe numbness and tingling in her feet, especially at night and even during the day. She is working more hours for her husband and watching their grandchild 3 days per week, and she is exhausted. The NP has several choices at this point: increase the dose of Neurontin because most patients will tolerate doses as high as 3600 mg/day, add another medication such as an opioid or an antidepressant, or add a second-line drug. After further questioning, the patient admits that she is feeling very stressed, but she denies depression. She is tolerating the Neurontin well with no lasting side effects. The Neurontin worked well initially, so the NP decides to increase the dose gradually to 600 mg tid (total dose 1800 mg/day), Again, she warns her about drowsiness.

For her return visit, the NP has several choices if AD's pain is not well controlled or if her insomnia is not improved. The NP could increase the Neurontin further, or she could add an antidepressant such as a TCA to help the patient sleep and to combat the neuropathic pain. The decision-making process at that point is best made in conjunction with the patient's wishes. If her pain becomes increasingly worse, the NP could also add an opioid for nighttime use. The plan of care would need to be based on the patient's nature and pattern of pain and insomnia, preferences, side effects of the other drugs, and her lifestyle.

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CONCLUSION 

For DPN, no one medication or regimen works for every patient. One medication from a drug class may be ineffective, whereas another medication from the same drug class relieves the pain. Sometimes drug combinations offer better pain relief and reduced side effects. Avoid polypharmacy and combination drugs that may exceed the recommended daily amounts such as Tylenol #3 or Tylox. Pain management plans need to be tailored for the individual patient.

Patient–prescriber contracts can help clarify the expectations of pain control, pain medications, and responsibilities of the patient and the provider. The contract can set limits on the amount of medication prescribed at one time so that continued visits are necessary for more pain medication, and the prescriber can monitor the amount of medication taken and evaluate side effects. If drug abuse is suspected, the patient should be confronted.

In some cases, pain relief cannot be adequately managed in primary care. When pain is unsuccessfully managed, more than three medications are indicated, or the dose of the medication continues to escalate, referral to a pain clinic is appropriate. Pain clinics have highly specialized health care providers who can follow patients closely. Most pain clinics will set up a contract with the patient to clarify the plan of care. They may also require drug testing to insure that patients are taking the prescribed medications especially if receiving high doses of opioids.

Researchers continue to explore the many pathways of pain. As scientists learn more about how the body reacts to painful stimuli, new treatments will become available to relieve pain. Research and development efforts will continue the quest for pain medications with fewer associated side effects and more specificity for neuropathic pain. By considering the specific symptoms experienced by the patient, other coexisting medical conditions, and the side effect profile of the medications, an effective treatment plan can be tailored specifically for each patient that will optimize pain management and maintenance of normal life activities.

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