Treatment of neuropathic pain in patients with chronic kidney disease.
After reading this article, the reader will be able to:
* Describe symptoms of neuropathic pain (NP)
* Describe common etiologies of NP in chronic kidney disease
* Understand the primary goal in treatment of NP is to make pain "bearable" or "tolerable", rather than total elimination of pain
* Compare and contrast currently available pharmacologic agents to treat NP.
Neuropathic pain (NP) is a chronic pain syndrome affecting the sensory peripheral afferent or central nerve fibres, or both (Baron, Binder & Wasner, 2010; Namaka et al., 2009). NP may be caused by damage to nerve fibres from drugs, diseases or injuries (Namaka et al., 2009). For patients with chronic kidney disease (CKD), NP is the most common neurological complaint (Krishnan, Pussell & Kiernan, 2009). Left untreated, NP can cause severe pain, impair function, and decrease quality of life (Haanpaa et al., 2009). The purpose of this article is to review the management of neuropathic pain with a focus on patients with CKD.
Diagnosis of NP is based primarily on patient history and physical examination. Presence of pain that is caused or initiated by a primary nerve lesion or nervous system dysfunction is essential for diagnosis of NP, according to the International Association for the Study of Pain (Moulin, et al., 2007). The signs and symptoms of NP are listed in Table 1. Simple questionnaires such as the S-LANNS (Bennett, Smith, Torrance, & Potter, 2005) and the physician administered Douleur Neuropathique 4 Questions (DN4) (see Figure 1) (Bouhassira et al., 2005) have been found to be valid and reliable for differentiating NP from other types of pain (Namaka et al., 2009). These questionnaires have been developed to classify neuropathic pain based on qualitative patient-reported pain descriptors (Baron, Binder & Wasner, 2010). However, these questionnaires have not been validated for use in the CKD and dialysis patient populations.
Table 1. Signs and symptoms of neuropathic pain
* Hot, burning, sharp, stabbing, cold, tingling, itching, numbness, "pins and needles"
* Shooting or radiating pain
* Pain often worse toward the end of the day
* Motor weakness around involved nerves
* Diminished or absence of deep tendon reflexes around involved nerves
* Inability to feel temperature, pressure or pain
* Inability to control heart rate or digestion (seen in diabetic neuropathy)
* Allodynia (increased pain in response to a normally non-painful stimuli, such as clothing rubbing against the skin)
* Hyperalgesia (increased pain in response to a normally painful stimulus)
Note: From Baron, Binder, and Wasner, 2010; Gilron, Watson, Cahill, and Moulin, 2006; Moulin et al., 2007.
Figure 1. Douleur Neuropathique 4 Questions (DN4)
To estimate the probability of neuropathic pain, please answer yes or no for each item of the following questions:
INTERVIEW OF THE PATIENT
Question 1: Does the pain have one or more of the following characteristics?
2. Painful cold
3. Electric shocks
Question 2: Is the pain associated with one or more of the following symptoms in the same area?
5. Pins and needles
EXAMINATION OF THE PATIENT
Question 3: Is the pain located in an area where the physical examination may reveal one or more of the following characteristics?
8. Hypoesthesia (reduced sense) to touch
9. Hypoesthesia (reduced sense) to pinprick
Question 4: In the painful area, can the pain be caused or increased by:
* Each "Yes" is 1 point. Each "No" is 0 points. A total score of[greater than or equal to] 4 is considered a positive test for neuropathic pain. The highest possible score is 10
Note. Original source: Bouhassira, D., Attal, N., Alchaar, H., Boureau, F., et al. (2005). Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). PAIN, 114(1), 29-36 (page 36, Appendix B).
This questionnaire has been reproduced with permission of the International Association for the Study of Pain[R] (IASP[R]).
Pathophysiology and associated medical conditions
Neuropathic pain is the result of a primary nerve lesion or nervous system dysfunction; many conditions can be associated with NP syndromes (Dworkin et al., 2010). Types of NP syndromes are diverse and may be divided into peripheral and central neuropathic pain syndromes based on the nerves affected (see Table 2, page 35). Common causes of NP in CKD patients are diabetic neuropathy and uremic neuropathy (Krishnan, Pussell & Kiernan, 2009). The pathophysiology of diabetic neuropathy is unclear. However, it is felt that high blood glucose levels could contribute to dysfunction in the peripheral nervous system via alteration of nerve cell metabolism (Donnan & Ledger, 2006). Uremia can contribute to dysfunction of the nervous system and subsequent NP. Peripheral neuropathy secondary to uremia typically develops only in advanced renal failure. It is hypothesized that high blood urea levels act as neurotoxins and cause demyelination and axonal degeneration of peripheral nerves (Palmer & Henrich, 2010). Other factors such as thiamine deficiency, hyperparathyroidism, and reduced plasma concentrations of biotin and zinc may contribute to development of uremic neuropathy (Palmer & Henrich, 2010). Peripheral neuropathy in patients with CKD can manifest as paraesthesias, weakness, muscle wasting, reduced or absent tendon reflexes or impaired sense of vibration. Neuropathy can also manifest as NP (Pop-Busui et al., 2010).
Table 2. Neuropathic Pain Syndromes
Peripheral Neuropathic Pain Syndromes
* Diabetic neuropathy
* Complex regional pain syndrome
* Post-herpetic neuralgia
* Chemotherapy-induced neuropathy
* Phantom limb pain
* Trigeminal neuralgia
* Uremic neuropathy
Central Neuropathic Pain Syndromes
* Central post-stroke pain
* Multiple sclerosis pain
* Parkinson's disease pain
* Spinal cord injury pain
Note. From Dworkin, A. (2002). An overview of neuropathic pain: Syndromes, symptoms, signs, and several mechanisms. The Clinical Journal of Pain, 18, 344.
NP occurs commonly among patients with CKD and receiving dialysis. It is estimated that 70% to 100% of dialysis patients will experience neuropathic symptoms despite reaching current targets for dialysis adequacy (Krishnan, Pussell & Kiernan, 2009). The incidence of uremic neuropathy appears to be less in patients with CKD not receiving dialysis. Typically, uremic neuropathy of clinical significance is not seen until the glomerular filtration rate drops below 12 mL/min (Krishnan, Pussell & Kiernan, 2009). Patients with CKD and diabetes are at a greater risk for developing NP. Diabetes is by far the most common causes of peripheral neuropathy. Greater than 40% of patients with diabetes will develop peripheral neuropathy within 10 years of disease onset (Donnan & Ledger, 2006).
Treatment of NP
NP is often a chronic condition that is difficult to treat. The primary goal for most patients is to make their pain "bearable" or "tolerable", rather than total elimination of pain. Secondary treatment goals include improving sleep, ability to function and overall quality of life (Moulin et al., 2007). Because of the chronic course of NP, it is important to recognize and treat common comorbidities such as anxiety and depression in NP patients.
Comparing different treatments for NP is difficult due to a lack of head-to-head trials. Therefore, one accepted approach is using the Number Needed to Treat (NNT) to estimate relative efficacy of individual treatments for NP. In this context, NNT is defined as the number of patients needed to receive a certain treatment in order to obtain one patient with at least 50% pain relief, based on a study or group of studies (Moulin et al., 2007). For example, if a particular medication had an NNT of three, that would mean that three patients would need to take that medication in order for one patient to have a 50% reduction in NP. Of note, most randomized controlled trials have involved patients with diabetic neuropathy or post-herpetic neuralgia. Therefore, the extent to which results may be extrapolated to other NP conditions, or to patients with CKD or receiving dialysis is limited.
Evidence for non-pharmacologic treatments for NP is limited. Some reports suggest that non-pharmacological treatments such as exercise, transcutaneous nerve stimulation, and cognitive behavioural therapy may offer modest benefit in NP. However, due to a lack of randomized controlled trial evidence, these treatments are not considered first-line (Gilron, Watson, Cahill, & Moulin, 2006).
Studies that evaluate the treatment of NP in patients with CKD and receiving dialysis are extremely limited in quantity and quality (Pop-Busui et al., 2010), so treatment recommendations for this patient population are based on extrapolation from studies that evaluate therapies to treat NP in the general population. Medications commonly used to treat NP are presented in Table 3.
Table 3. Pharmacotherapy for neuropathic pain in chronic kidney disease Drug Dosage for CKD Advantages (Brand Name) Tricyclic antidepressants Amitriptyline 10 to 150 mg daily * Improvement of (Elavil *) depression and sleep disturbance Nortriptyline 25 to 150 mg daily * Less expensive than (Pdmelor *) newer agents Desipramine 25 to 100 mg daily * Convenience of once (Norpramit *) daily dosing * Dose adjustment not required in chronic kidney disease Anticonvulsants Pregabalin 25 to 75 mg daily (dosed * Rapid dose titration (Lyrica *) post-dialysis) schedule (3 weeks) * May have fewer adverse effects than gabapentin * No clinically significant drug interactions * Convenience of once-daily dosing * Rapid dose titration over 3 weeks Gabapentin 100 to 300 mg daily * Improvement of sleep (Neurontin *) (dosed post-dialysis) disturbances * No clinically significant drug interactions * Less expensive than pregabalin * Convenience of once-daily dosing Carbamazepine 200 to 600 mg daily in * Dose adjustment not (Tegreto *) two divided doses required in chronic kidney disease * Improvement of sleep disturbances * Less expensive than newer medications Serotonin Norepinephrine Reuptake Inhibitors (antidepressants) Venlafaxine 37.5 mg to 150 mg daily * Improvement of (Ejfexor *) (dosed post-dialysis) depression Duloxetine Not recommended for (Cymbaltc *) patients on dialysis Opioid Analgesics Tramadol 50-200 mg daily in * Rapid onset of (Ultran *) divided doses (immediate analgesic effect release formulations only) * May have less constipation and nausea than weak opioid agonists such as codeine Opioids Varies by medication. Use * Rapid onset of (morphine, lower doses of oxycodone analgesic effect oxycodone, in chronic kidney codeine, disease methadone, etc.) * Option to convert to long-acting dosage forms from short-acting dosage forms * May be used in combination with first-line agents Topical Anaesthetics Lidocaine 5-10% topical cream or * No systemic side (Xylocaine *) gel up to three times per effects day * May be used in combination with oral agents * No significant drug interactions Drug (Brand Name) Disadvantages Tricyclic antidepressants Amitriptyline * Adverse effects: sedation, anticholinergic (Elavil *) effects (e.g., confusion, dry mouth, urinary retention, constipation, blurred vision), weight gain, orthostatic hypotension, potential for arrhythmia Nortriptyline * Contraindicated in patients with significant (Pdmelor *) cardiovascular disease, glaucoma, symptomatic prostatic hypertrophy Desipramine * Requires slow dose titration (6-8 weeks) to (Norpramit *) minimize adverse effects * Daytime sedation may increase fall risk for elderly * Risk of serotonin syndrome when taken with other antidepressants Anticonvulsants Pregabalin (Lyrica * Adverse effects: sedation, dizziness, *) peripheral edema, weight gain * Not an insured benefit under many drug insurance plans * May cause exacerbation of heart failure Gabapentin * Adverse effects: sedation, dizziness, (Neurontin *) peripheral edema, weight gain, visual blurring * Slow titration schedule required to reach effective dose (8-12 weeks) Carbamazepine * Adverse effects: sedation, dizziness, (Tegreto *) constipation, nausea, ataxia, blood dycrasias, hepatotoxicity. * Monitoring of blood counts and liver function tests required. * May cause serious dermatologic reactions including Stevens-Johnson syndrome. * Drug interactions Serotonin Norepinephrine Reuptake Inhibitors (antidepressants) Venlafaxine * Adverse effects: nausea, dry mouth, elevated (Ejfexor *) blood pressure (greater risk with higher doses), constipation, hyperhydrosis Duloxetine * Withdrawal syndrome with abrupt (Cymbaltc *) discontinuation * Risk of serotonin syndrome when taken with other antidepressants Opioid Analgesics Tramadol (Ultran * Adverse effects: nausea, vomiting, *) constipation, dizziness, sedation, may lower seizure threshold * Risk of serotonin syndrome when taken with antidepressants * More expensive than weak opioid analgesics Opioids (morphine, * Adverse effects: nausea, vomiting, oxycodone, constipation, dizziness, sedation, urinary codeine, retention methadone, etc.) * Use with caution in patients with a history of substance abuse * Not an insured benefit under many drug insurance plans Topical Anaesthetics Lidocaine * Adverse effects: local erythema, rash (Xylocaine *) Note: From Baron, Binder and Wasner, 2010; Dworkin et al., 2010; Moulin et al., 2007; Namaka et al., 2009; Pop-Busui et al., 2010; Product monograph duloxetine; Product monograph pregabalin; Product monograph venlafaxine; Product monograph gabapentin
First-line therapy for NP includes certain medications from two drug classes: antidepressants and anticonvulsants.
Tricyclic antidepressants (TCAs)
TCAs have the best evidence for efficacy for the treatment of NP (Moulin et al., 2007). This class of medications is thought to exhibit an analgesic effect through blockade of N-methyl-D-aspartate agonist-induced hyperalgesia. Antagonist effects on noradrenaline and serotonin reuptake and sodium channels may also play a role. The estimated NNT for TCAs from existing literature is 2.5. The NNT does not differ between TCAs with balanced reuptake inhibition of serotonin and noradrenaline (amitriptyline) and those relatively selective for noradrenaline reuptake inhibition (desipramine, nortriptyline). Efficacy is maintained across various etiologies of NP (e.g., diabetic neuropathy, herpes zoster, stroke, etc.) (Namaka et al., 2009).
Use of TCAs is limited by their anticholinergic effects, such as constipation, urinary retention, blurred vision, delirium, dry mouth and sedation. TCAs are contraindicated in patients with cardiac disease, closed-angle glaucoma, and seizure disorders due to their anticholinergic effects (Baron, Binder, & Wasner, 2010). Desipramine and nortriptyline appear to be better tolerated in the elderly due to fewer anticholinergic effects. Should a TCA be selected, it is recommended to start with a low dose and titrate slowly. Patients with CKD and receiving dialysis should be counselled about side effects of TCAs, especially dry mouth and orthostatic hypotension. Dialysis patients are fluid-restricted, and dry mouth may increase their desire to drink (Donnan & Ledger, 2006). Alternative remedies for relief of dry mouth include saline spray or sucking on hard candies or ice cubes. TCAs should be dosed at bedtime to avoid daytime drowsiness.
Gabapentin mediates analgesic effects through blockade of voltage-dependent calcium channels in the dorsal-horn neurons (Namaka et al., 2009; Moulin et al., 2007). This blockade of voltage-dependent calcium channels down-regulates release of excitatory neurotransmitters, such as glutamate and Substance P, and therefore decreases NP symptoms. Compared to placebo, the estimated NNT for gabapentin is 4, while the NNT for pregabalin is 4.2 (Moulin et al., 2007).
Pregabalin is the only anticonvulsant that has Health Canada approval for treatment of NP (Namaka et al., 2009). Pregabalin and gabapentin exhibit similar mechanisms of action at voltage-dependent calcium channels. However, the affinity of pregabalin for voltage-dependent calcium channels is seven times that of gabapentin. This allows lower doses of pregabalin to deliver similar analgesic effects as higher doses of gabapentin (Namaka et al., 2009).
Both gabapentin and pregabalin require dose adjustment in patients with renal impairment, and slow dose titration in order to avoid adverse effects (see Table 3). For patients with CKD and receiving dialysis, these medications are removed by hemodialysis and should be given post dialysis (Product monograph, gabapentin; Product monograph, pregabalin).
Carbamazepine is the drug of choice for trigeminal neuralgia, but is not recommended as first-line management for other types of NP due to significant adverse effects such as hepatotoxicity and blood dyscrasias (Moulin et al., 2007; Gilron, Watson, Cahill, & Moulin, 2006).
Venlafaxine is a serotonin norepinephrine reuptake inhibitor antidepressant that does not appear to be as effective as TCAs for NP. Current literature suggests that the NNT for venlafaxine when used for treatment of NP is 4.6, versus 2.5 with TCAs (Moulin et al., 2007). Venlafaxine has shown efficacy for NP at doses of 150 mg to 225 mg per day in the normal population (Moulin et al., 2007). In patients with CKD receiving hemodialysis, the dose of venlafaxine should be reduced and given post dialysis (Product Monograph: venlafaxine). Because venlafaxine has less affinity for histaminic, muscarinic, and adrenergic receptors than TCAs, patients experience fewer adverse effects with venlafaxine (Namaka et al., 2009). The favourable side effect profile of venlafaxine may warrant its use over TCAs.
Duloxetine is another serotonin norepinephrine reuptake inhibitor antidepressant, and has been approved for the treatment of NP secondary to diabetic neuropathy (Product Monograph: duloxetine). However, because duloxetine has not been studied in patients with CKD receiving hemodialysis, use in this patient population is not recommended due to lack of safety data (Product Monograph: duloxetine).
Topical lidocaine 5% gel or cream is useful alone or in combination with oral medications for localized NP. The NNT for topical lidocaine is 4 (Moulin et al., 2007). Relief of NP with topical lidocaine is attributed to blockage of neuronal sodium channels by lidocaine. Topical lidocaine is attractive because it provides relief of NP for up to eight hours and has minimal systemic side effects (Moulin et al., 2007). As lidocaine patches are not available in Canada, a topical gel or cream is used.
Opioids may be considered for NP symptoms after other treatments have been tried. A recent systematic review found that controlled-release morphine and controlled-release oxycodone demonstrated a 20% to 30% reduction in pain intensity for NP. The NNT for morphine and oxycodone is 2.5 (Moulin et al., 2007). Opioids may be used as monotherapy or in combination with first or second-line treatments for NP. Opioids should be started at a low dose and titrated upward, as needed. Instant release formulations of opioids should be used first. When an effective dose for control of NP is reached, the patient may be switched to an equivalent dose of a continuous-release opioid formulation. The opioid analgesics morphine and oxycodone do not need to be dose adjusted in CKD patients receiving hemodialysis (Product Monograph: morphine, Product Monograph: oxycodone). Patients and health professionals should be aware of a potential for abuse and/or dependence with the use of opioids for NP.
Tramadol is a "non-opioid agonist." In addition to its non-selective serotonin and norepinephrine reuptake inhibitor actions, tramadol acts as a weak agonist at the mu opioid receptor via an active metabolite (Donnan & Ledger, 2006; Product monograph, tramadol). In clinical trials, the NNT for tramadol is 3.8 (Moulin et al., 2007). Tramadol is available in a combination product with acetaminophen 325mg and tramadol 37.5 mg. Patients taking the combination product should be counselled on using caution when taking other products that contain acetaminophen. The maximum dose of 4 g of acetaminophen per day should not be exceeded (Donnan & Ledger, 2006). Taking tramadol with other medications that increase serotonin levels, such as antidepressants, will increase the patient's risk of serotonin syndrome (Donnan & Ledger, 2006). Tramadol should, therefore, not be used in combination with selective serotonin reuptake inhibitors (for example, citalopram) or other antidepressants such as venlafaxine when used for the treatment of NP. Tramadol requires a dose reduction for patients with CKD or receiving dialysis (Product Monograph: tramadol).
Implications for practice
The treatment of NP requires patience, time and patient education within a multidisciplinary team environment. For patients with CKD and receiving dialysis, the frequent contact with health care professionals can provide regular opportunities to assess pain and response to therapy. In order to evaluate the efficacy of any medication for NP, health professionals can ask about pain intensity before and after the medication is started. Instruments that can be used include a visual analogue scale (where a patient marks on a 10 cm line where their pain rating is) or a numeric scale that ranges from "no pain" to "the worst possible pain" (Namaka et al., 2009, Pop-Busui et al., 2010). Assessment for efficacy should occur generally approximately every six to eight weeks (Namaka et al., 2009). It is also important to titrate many medications for NP slowly, especially in patients with CKD and receiving dialysis in order to avoid adverse effects, such as dizziness and drowsiness. Medications should be added in sequence (first-line therapies, followed by second, then third line) with adequate time for evaluation for efficacy and toxicity (Moulin et al., 2007).
Patient education is also very important to the treatment of NP. Patients need to be aware that NP is a chronic condition that is not "cured", rather it is reduced to a more tolerable level. Often, multiple medications or combinations of medications may be tried before achieving a reduction in pain (Namaka et al., 2009). As NP is chronic, it is likely that patients will continue to take medications, even if pain is reduced to a manageable level.
Baron, R., Binder, A., & Wasner, G. (2010). Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurology, 9, 807-819.
Bennett, M.I., Smith, B.H., Torrance, N., & Potter, J. (2005). The SLANSS score for identifying pain of predominantly neuropathic origin: Validation for use in clinical and postal research. The Journal of Pain, 6(3), 149-158.
Bouhassira, D., Attal, N., Alchaar, H., Boureau, F., Brochet, B., Bruxelle, B., ... Vicaut, E. (2005, March). Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain, 114(1-2), 29-36.
Donnan, J., & Ledger, S. (2006). An update on the treatment and management of diabetic peripheral neuropathy. CANNT Journal, 16, 32-36.
Dworkin, R.H., O'Connor, A.B., Audette, J., Baron, R., Gourlay, G. K., Haanpaa, M.L., ... Wells, C.D. (2010). Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clinic Proceedings, 85(3 Suppl.), S3-14.
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Palmer, B.F., & Henrich, W.L. (2010). Uremic polyneuropathy. UptoDate Version 18.2.
Pop-Busui, R., Roberts, L., Pennathur, S., Kretzler, M., Brosius, F.C., & Feldman, E.L (2010). The management of diabetic neuropathy in CKD. American Journal of Kidney Diseases, 55, 365-385.
Product Monograph: Cymbalta[R], duloxetine. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: venlafaxine. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: pregabalin. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: morphine. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: gabapentin. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: oxycodone. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Product Monograph: tramadol. (2010). Greenwood village CO: Thomson Reuters Healthcare Series 2.0 (Micromedex)
Contact hour: 2.0 hrs
Heather K. Naylor, BScPharm, ACPR, Pharmacist--Manitoba Renal Program, Winnipeg Regional Health Authority, Winnipeg, MB.
Colette B. Raymond, PharmD, MSc, ACPR, Clinical Pharmacist--Manitoba Renal Program, Winnipeg Regional Health Authority, Winnipeg, MB.
Address correspondence to: Heather Naylor, BScPharm, Department of Pharmaceutical Services, Seven Oaks General Hospital, 2300 McPhillips Street, Winnipeg, MB R2V 3M3. Email: firstname.lastname@example.org
Submitted for publication: January 11, 2011. Accepted for publication in revised form: February 5, 2011.
By Heather K. Naylor, BScPharm, ACPR, and Colette B. Raymond, PharmD, MSc, ACPR
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|Author:||Naylor, Heather K.; Raymond, Colette B.|
|Date:||Jan 1, 2011|
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