Medications> Neuropathy and bladder disorders>

INDICATIONS

• Pregabalin for painful diabetic polyneuropathy (DPN)
• Duloxetine for painful DPN

• Gabapentin most commonly used non-FDA approved medication (Backonja).
• Non FDA-approved DPN pain medications include anti-depressants, opiates or opiate-like agents and anti-epileptic medications.
• Anti-depressants include tricyclic antidepressants (amitriptyline, nortriptyline) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs:  duloxetine, venlafaxine).
• Anti-epileptic medications include gabapentin, lamotrigine, carbamazepine, phenytoin and lacrosamide
• Opiate or opiate-derivative agents include oxycodone, hydromorphone, fentanyl and tramadol.
• Other agents include topical agents (lidocaine cream, lidoderm patches, capsaicin cream, neutriceuticals (Metanx, alpha-lipoic acid) and devices (spinal stimulators, TENS).

MECHANISM

• Pregabalin: GABA analog that does modify GABA function, but rather has affinity for the alpha2-delta subunit of voltage-gated calcium channels
• Duloxetine: selective serotonin and norepinephrine reuptake inhibitor
• Gabapentin: similar to pregabalin with differences noted below

USUAL ADULT DOSING

• Pregabalin: start 50 mg three times a day, then titrate to 100 mg three times a day if tolerated after one week. Pregabalin ~6 times more potent than gabapentin (i.e. 1800 mg gabapentin = 300 mg pregabalin) with more rapid onset. Can be dosed twice a day. Has linear pharmacokinetics (different than gabapentin) and faster onset of action that gabapentin.
• Duloxetine: start 30 mg for one week, then increase to 60 mg if needed. Doses >60 mg/day have relatively modest additional pain relief but associated with more side effects. Benefit as early as 1-2 weeks after initiating treatment but continues until 4-6 weeks before plateauing. Taken once daily in morning since bedtime doses can result in insomnia.
• Gabapentin: start 300mg (one tablet) at bedtime, additional tablets added first at the morning dose, then in the afternoon with dose increased every 2-3 days. Stop titration if patients either experience pain relief or develop side effects such as sedation. The average effective dose 1800 mg/day given in three divided doses of 600mg. Higher doses (up to 5 grams/day) can have additional benefit in some patients.
• Tricyclic antidepressants: amitriptyline is the prototype. Requires long titration schedules of 6-8 weeks before efficacy seen (Wernicke).
• Anti-epileptic agents: similar pain relief as gabapentin or pregabalin but with more side effects (i.e. phenytoin (Sindrup)). Many older agents also require monitoring of serum levels with potential bone marrow toxicity and multiple drug interactions.
• Opiate and opiate-like agents: can be given alone or in combination with acetominophen for synergistic effects, allowing for similar pain relief with lower doses of opiate type agents.
• Topical agents: no systemic absorption and lower rates of side effects or drug interactions. Capsaicin applied to the painful area 2-4 times per day. Lidoderm patches applied to painful areas on a 12 hour on/off schedule.
• Neutraceuticals: supplements have not been systematically studied in controlled trials. Exception is alpha lipoic acid which demonstrates benefit on neuropathy severity, with trend towards improved symptoms at >600 mg daily using pharmaceutical grade alpha lipoic acid (not available in US) (Ziegler).
• Devices: spinal cord stimulators not associated with systemic side effects although invasive and expensive. Additional studies needed (Tesfaye). Other approaches being investigated include near infrared light therapy. Not subject to FDA approval process with potential for inappropriate marketing.

FORMS

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Duloxetine not recommended for GFR < 30 mL/min. 
• See Tables 2 and 3 below needed for gabapentin and pregabalin renal dosage adjustments

• Duloxetine is hepatically metabolized; use with caution in liver disease.

• All (gabapentin, pregabalin, duloxetine) Category C

• All: infant risk cannot be ruled out (Thomson)

ADVERSE DRUG REACTIONS

• Duloxetine CONTRAINDICATED with concomitant use of MAO inhibitors, and black box warning for pediatric patients.

• Pregabalin: edema, weight gain, constipation, increased appetite, sedation, dizziness
• Gabapentin: edema, sedation, dizziness, fatigue, fever
• Duloxetine: constipation, dizziness, headache, sedation, fatigue, nausea, dry mouth

• Pregabalin: angioedema (especially with concomitant ACE inhibitor use) can be serious
• Gabapentin: Stevens-Johnson syndrome, suicidal thoughts, drug induced coma

DRUG INTERACTIONS

• Gabapentin and pregabalin have no major drug interactions that require dosage adjustments.
• Duloxetine is contraindicated with MAO inhibitors (i.e. isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine)
• Pregabalin may increase risk of angioedema with concomitant use of ACE inhibitors.

PHARMACOKINETIC

COMMENTS

• General principles: start with the lowest effective dose and titrate; higher doses generally associated with increasing side effects.
• Treatment focused on reducing pain levels [ i.e. level of ~3 on a 0 to 10 visual analog scale (VAS)] to improve quality of life and functional limitations, rather than complete pain resolution which is less realistic.
• In general, number needed-to-treat analyses suggest that neuropathic agents have similar degrees of efficacy, so side effect profiles, titration schedules, potential drug interactions and cost often play a central role in choosing an agent.
• Gabapentin and pregabalin are not hepatically metabolized and are attractive in patients with liver disease.
• Pregabalin with concomitant use of thiazolidinediones increases risk of weight gain and edema.
• Combining agents from different classes results in synergistic effects (Gilron 2005, Gilron 2009) and lower doses of medications from the opiate, anti-depressant class and anti-epileptic classes.
• Anti-inflammatory agents that are effective in treating inflammatory pain are generally not helpful for neuropathic pain.

Basis for Recommendations

• Wernicke JF, Pritchett YL, D'Souza DN, et al.; A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain.; Neurology; 2006; Vol. 67; pp. 1411-20;
  ISSN: 1526-632X;
  PUBMED: 17060567
  Rating: Basis for recommendation
  Comments:One of the registration trials for duloxetine.
  
  
• Rosenstock J, Tuchman M, LaMoreaux L, et al.; Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial.; Pain; 2004; Vol. 110; pp. 628-38;
  ISSN: 0304-3959;
  PUBMED: 15288403
  Rating: Basis for recommendation
  Comments:One of the FDA registration trials for pregabalin.
  
  
• Backonja M, Beydoun A, Edwards KR, et al.; Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.; JAMA; 1998; Vol. 280; pp. 1831-6;
  ISSN: 0098-7484;
  PUBMED: 9846777
  Rating: Basis for recommendation
  Comments:The first trial to demonstrate pain relief with gabapentin. Many subsequent trials adopted the same design.
  
  

REFERENCES

RELATED MODULES

• Peripheral Neuropathy