#58 Analgesics for PN

This is a summary of analgesics only and does NOT have all the possible information about the medications listed below. This is not individual medical advice and does not substitute for medical advice.  The information below does not assure that the medications are safe, effective, or appropriate for you. Always consult your health care professional(s) for complete information about any medication and your specific health needs.

Peripheral Neuropathy is nerve damage to Motor, Sensory and Autonomic nerves that connect the spinal cord to muscles, skin and internal organs.   When the Sensory nerves are affected, symptoms include pain often described as tingling, burning, electric shock, pinching, deep bone pain or pins & needles.  These symptoms of pain are often severe.

This article will look specifically at the analgesics, also referred to as the pain killers, used to treat neuropathic pain.

There are a variety of analgesics that work in a variety of ways in the body.  They are used to reduce and potentially relieve pain.  For example, some analgesics work by reducing signals from the nerves to the brain; others affect how the brain interprets and responds to these signals. Others work on blocking chemicals.   Analgesics have various categories based on how they affect and reduce pain.  Some analgesics can be obtained OTC (Over the Counter), while others require a prescription.  Some prescriptions are controlled substances and require a triplicate prescription.  Analgesics can also act to address both pain and inflammation.

To ensure maximum effectiveness of treatment for neuropathic pain, the health care provider and patient work together to develop a customized treatment plan.  Below are things to consider when looking at which analgesics to use:

• Consider the cause and severity of neuropathic pain. 
• What are the symptoms and their impact on the person’s daily life (affecting sleep, relationships, productivity, emotions, depression, and mobility).
• Assess the risk, side effects and benefits of the medication(s) being considered.
• Take into account the age of the patient; allergies; drug interactions; breastfeeding; other medications and supplement interactions; other medical conditions i.e. anemia, cardiac, respiratory, liver or kidney disease, stomach ulcers etc.
• Engaging in ongoing, long-term evaluation of treatment, and discussion of other treatment options.  It’s important to note that analgesics are only one option in the overall treatment of neuropathic pain. 
• Consider referral to specialists, Chiropractors, Occupational Therapists, Physiotherapist or other health care provider that works to reduce symptoms.

Remember:

• Do not share your medications with others.  Sharing is against the law.
• Tell all your doctors, including your dentist, what medications you take.
• Keep all your medications in a safe place, out of the reach of children.
• Let your doctor know if you are pregnant or become pregnant.

OVER THE COUNTER (OTC):

Over-the-counter analgesics can help treat mild to moderate pain associated with peripheral neuropathy. Generic versions are typically available and at a reduced cost.

 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs):  These medications not only reduce mild to moderate pain they also reduce swelling and fever. They do so by blocking the body’s production of certain natural substances that cause inflammation.  The list of potential side effects is lengthy, yet it is very important to take the time to review it. You may not know sensitivity to sun has been reported, or the medication passes into breast milk. NSAIDS may cause stomach upset, allergic reaction and may delay healing.  It’s important to talk with your health care provider if you are over 65, anemic or have existing heart, stomach, kidney, liver or intestinal disorders.  While NSAIDS may increase the risk for heart attack or stroke, Aspirin actually prevents blood clots from forming.  These medications work best if they are taken when early signs of pain begin.  Often, if you wait until the pain increases you may find the medication does not work as well. 

• Ibuprofen – Common brand names Advil®, Motrin®, Midol®
• Naproxen – common brand names Aleve® Naprosyn®
• Ketoprofen – common brand name Orudis®
• Aspirin common brand names Bayer® Bufferin® Ecotrin® Excedrin®, St. Joseph’s®

ACETAMINOPHEN: works to reduce pain, but they do know it does not target inflammation as NSAIDS do; nor is it as likely to cause stomach upset and other side effects.  Acetaminophen has been linked to liver failure when used excessively for long periods of time⁽¹³⁾  and can increase the risk for kidney damage over time.   

• Common brand names Tylenol® and Paracetamol®

TOPICAL MEDICATIONS

TOPICAL:  Topicalanalgesics come in the form of creams, ointments, foams, gels, lotions, sprays and transdermal patches that you apply directly on your skin.  The active drug(s) in these topicals are absorbed through the skin and provide localized pain relief. To be most effective, topicals must be applied 3 – 4 times a day; and may take weeks to notice the full potential of their benefits.  The first use should be a small amount in a small area to check for possible allergic reaction or a burning side effect.  Do not apply on scraped, burned, irritated skin or to open wounds on the skin.   Be sure to wash your hands after applying.  Topical analgesics can be OTC or prescription. 

OTC:

• Capsaicin (#28 100+ Things) – common brand names Capzasin-P®, Dolorac®, Zostrix® LivRelief®).  This is a substance made from the seeds of hot chili peppers.  It provides temporary relief from minor pain located close to the skin’s surface. ⁽¹⁾   Adverse reactions include skin irritation, contact dermatitis, and even coughing.
• Diclofenac – common brand name is Voltaren®.  Diclofenac is an NSAID and is not advised for long term use.
• Lidocaine (#54 100+ Things) – common brand name Solarcaine® When applied on the skin surface Lidocaine is used to treat areas of pain by working as a local anesthetic. Care must be taken as a topical Lidocaine can be absorbed through the skin and enter the bloodstream if too much is used too often. 5% can be purchased without a prescription.

PRESCRIPTIONS:  WHEN OTC TOPICALS ARE NOT ENOUGH

Analgesic medications that require a prescription do so when the medication being used is a controlled substance.  When OTC pain medications don’t provide satisfactory relief of neuropathic pain, or several factors are impacting the neuropathic pain, you can speak to your family physician to discuss options for medication(s) that require a prescription.

TOPICAL PRESCRIPTIONS:    Prescription topicals come in applications that are rubbed on, sprayed on, and in extended release patches.

• Diclofenac – prescription strength
• Lidocaine (#54 100+ Things) – prescription strength

TOPICAL COMPOUNDS (Mamchur, S. 2018-11-21)

Compounds have more than one medication in the cream or base substance.  This requires a pharmacy with the capability to create a compound.  Apply a pea size amount 3 times per day for best results.  An example of what your doctor may prescribe in a compound for nerve pain may consist of

• Ketoprofen 10%/ Gabapentin 10%/ Lidocaine 5%. (Ketoprofen requires a regular prescription) 
• Ketamine 10%/ Gabapentin 10%/ Lidocaine 5%: (Ketamine requires a triple prescription)

A prescription compound for joint or muscle pain may consist of: 

• Ketoprofen 10%/Cyclobenzaprine 2%/Pentoxifyline 2%

TRANSDERMAL PATCHES

Transdermal Patches use opioids such as Buprenorphine or Fentanyl that are delivered via the patch through the skin.  It is used for severe pain over an extended period of time.

• Buprenorphine, brand name Butrans® The higher strengths of Butrans (7.5, 10, 15, or 20 micrograms per hour patches) should be used only if you have been regularly taking moderate amounts of opioid pain medication. These strengths may cause overdose (even death) if used by a person who has not been regularly taking opioids. 

• Fentanyl, brand name Duragesic® It is a high alert drug; and can lead to fatal respiratory depression.  (Alberta Health Services)

OPIOIDS

Opioids are also referred to as narcotics.  There are several forms (tablets, capsules, liquid, suppositories, injectable) and strengths available, and they come in both short and longer acting formulas. Opioid medications are prescribed for moderate to severe pain and are currently the subject of great uncertainty to their effectiveness in treating neuropathic pain.  There is a belief that opioids are not effective long term, and there are concerns around misuse within the opioid crisis.  Yet, According to Fudin et al (2017) many opioids have shown efficacy in reducing peripheral neuropathic pain.  They further narrow the effective opioids listing Tramadol, Tapentadol (Nucynta), Methadone and Levorphanol as having well established mechanisms to substantially reduce neuropathic pain. 

Side Effects:  Opioids have potential side effects like all medications.  It’s important to be aware of what they are and to know they vary with each type of medication and vary for each individual. Side effects can often be managed, but it may come to having a discussion with your prescribing health care worker if the side effects outweigh the benefits. 

Tolerance:  This term describes when the body gets use to a medication.  The medication is no longer providing adequate relief and requires having the dose either increased, or consideration given to adding a supplemental medication or switching to another medication.

Physical Dependence:  Where the body has adjusted to the medication and has become physically dependent on it.  If a person is to suddenly stop the medication the person would experience withdrawal symptoms such as chills and sweats, abdominal cramping, vomiting, even seizures.

Addiction:  Impaired physiological, psychological and social control of using a drug.  Inherently there is a craving and compulsive need for the drug despite any harm.  Opioids have a risk for abuse and addiction.

Interactions:  It is strongly advised not to use alcohol or cannabis when taking Opioids as it may amplify symptoms of dizziness and/or drowsiness.  Be sure to talk with your prescribing health care provider the possible drug interactions as there are many and may lead to slow/shallow breathing, light-headedness, severe drowsiness or dizziness.

It is becoming more common to be provided with a Naloxone kit when prescribed an Opioid.  Naloxone is used to treat opioid poisoning caused by an overdose.  It is recommended to share information with family/household members on the signs of an overdose and how to treat it with Naloxone.  Naloxone works within 2 – 5 minutes and a call to 911 should be made.

Drug abuse and misuse may occur, drug monitoring is recommended.

The more common opioids prescribed are:

Codeine:  Codeine is taken orally and acts on the Central Nervous System (CNS) changing how your body feels and responds to pain.  When used for a long time the body may build up a tolerance and will appear it has stopped working.  It is advised to take the lowest effective dose, and for the shortest time possible. Taking codeine can be habit forming and has a risk for abuse.  It is not advised for children under 18 years of age. 

Tramadol:  common brand name Ultram® has properties similar to both opioids (narcotics) and antidepressants.  Tramadol reduces moderate to severe pain by interfering with pain signals to the brain (like an opioid) and by affecting neurotransmitters (like an antidepressant).  It is known to effectively reduce neuropathic pain.  If you are taking an opioid, then tramadol may be used for breakthrough pain. Be aware of the precautions when taking Tramadol like pre-existing health conditions, especially cardiac concerns as Tramadol may cause a condition that affects the rhythm of the heart.

Tapentadol:  common brand name Nucynta is used for short term pain.  It also comes in an Extended Release form Nucynta ER for longer term pain.  Studies have shown Nucynta is effective in reducing neuropathic pain associated with diabetic peripheral neuropathy. ⁽⁹⁾ The extended release form is for around-the-clock treatment of pain that is not controlled by other medicines.  You should not use this medication if you are allergic to it or have severe asthma or breathing problems, or if you are prone to constipation. 

Morphine:  acts on the central nervous system and has the risk of dizziness or light-headedness when rising from a sitting or lying position.  It is advised to get up slowly. 

Oxycodone: as with other opioids, the removal of oxycodone from the body can be affected by other medications.  Be sure to follow your prescribing health care provider’s directions and don’t hesitate to ask questions.  You can also ask your pharmacist any questions you may have on any prescription.  Avoid ingesting grapefruit when taking oxycodone as it may increase side effects.

Hydromorphone: common brand name Dilaudid is sometimes used for sudden breakthrough pain when a long acting opioid is already being used regularly.  Liquid forms may contain sugar and caution is advised if you are diabetic.

Fentanyl:  Is often used for breakthrough cancer induced neuropathic pain when already taking a moderate to large amount of opioid medication.  Different forms of Fentanyl i.e. lozenges, buccal tablets, patches) are not to be substituted for each other as they do not have the same effects at equal strengths.    Fentanyl should not be used if there is severe asthma or other breathing problem as it is known to cause respiratory depression.  It also can lead to a bowel obstruction or paralytic ileus.  If taking as a tablet do not break, bite, chew, suck or swallow the tablet whole.  Take as directed, normally by placing the tablet in your mouth under the tongue or above a rear molar between the upper cheek and your gum.  Let it dissolve.  Avoid grapefruit.

Methadone:   is used for moderate to severe pain and it is also used to treat opioid addiction. Methadone helps prevent withdrawal symptoms when stopping other opioids.  It may also cause a condition affecting the heart rhythm called QT prolongation.  Be aware liquid methadone may contain sugar and/or alcohol that can adversely affect diabetes, alcohol dependency, and liver disease.

Ketamine:   Controversy over whether Ketamine is an opioid was stirred when Stanford University researchers discovered Ketamine works like an opioid by activating opioid receptors in the brain (Anson, 2019).  Ketamine is also used to treat depression when there isn’t adequate response to more common anti-depressants.  Ketamine has been effective in reducing severe pain (i.e. cancer-induced neuropathic pain).  Primary adverse effects are on the central nervous system causing sedation, decreased respirations, overstimulation of senses, feelings of disassociation, and it’s possible it can stimulate mood disorders, as well as neurotoxicity (AHS).  It is strongly advised to be used in select patients, under close supervision when other analgesic medications have not been effective.

Levorphanol: is a potent synthetic opioid used when other pain medications did not work well enough or cannot be tolerated.  Levorphanol is similar in action to morphine, however, it is up to 8 times more potent than morphine.

Buprenorphine:  common brand name Subutex when taken sublingually (placed under the tongue) it does not suppress the immune and endocrine (gland and hormone) systems as much as other long-acting opioids. Buprenorphine has shown to effectively treat chronic pain in cases where other opioids are not effective.  However, switching to this medication from other opioids often requires abstaining from the other opioid for 12-48 hours. To avoid the need to abstain, the Butrans patch (brand name for the transdermal patch) can be used as a bridge medication to transition to sublingual buprenorphine without withdrawal symptoms or other adverse effects.  Buprenorphine is also used in treatment programs for drug abuse.

Epilogue

Doctors will often prescribe a combination of medications consisting of an analgesic, an anti-depressant (#16 100+ Things), and an anti-convulsant.  In more recent years, doctors are using Medical Cannabis ( #36 100+ Things) to treat neuropathic pain.

Additional Resources

Dr. Charles Argoff:  “Opioids as Treatment for Neuropathic Pain”   

Provided by the Foundation For Peripheral Neuropathy is a list of commonly prescribed neuropathic pain medications that you can view, including starting and maximum dosage, side effects, precautions, interaction and other benefits, click here. ⁽¹⁾

References

1. Alberta Health Services   albertahealthservices.ca Fentanyl-patch     
2. https://www.foundationforpn.org/what-is-peripheral-neuropathy/treatments/
3. https://www.webmd.com/drugs/2/drug-155153/butrans-transdermal/details. ©2016, WebMD, LLC. All rights reserved.
4. https://www.webmd.com/drugs/2/drug-18497-6298/fentanyl-citrate-buccal/fentanyl-lozenge-buccal/details
5. https://www.webmd.com/drugs/2/drug-155204/fentanyl-citrate-sublingual/details
6. https://www.webmd.com/drugs/2/drug-159202/fentanyl-sublingual/details
7. https://www.emedicinehealth.com/drug-fentanyl_transdermal_skin_patch/article_em.htm
8. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/19813s039lbl.pdf
9. https://www.emedicinehealth.com/drug-methadone/article_em.htm
10. https://www.foundationforpn.org/?s=Nucynta
11. https://www.emedicinehealth.com/drug-tapentadol/article_em.htm
12. https://www.emedicinehealth.com/drug-tramadol/article_em.htm
13. https://www.britannica.com/science/analgesic
14. https://cen.acs.org/articles/92/i29/Does-Acetaminophen-Work-Researchers-Still.html
15. https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/in-depth/pain-medications/art-20045004
16. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20044970
17. https://ca.video.search.yahoo.com/yhs/search?fr=yhs-trp-001&hsimp=yhs-001&hspart=trp&p=opiods#id=2&vid=deaa72720344c7b1e3cd805a2a7fa961&action=click
18. Anson, P.( 2019-08-17):  Is Ketamine an Opioid.  Pain News Network. https://www.painnewsnetwork.org/stories/2019/8/16/is-ketamine-an-opioid
19. Argoff, Charles, MD. (2012-04-19). The Use of Opioids as a Treatment for Neuropathic Pain.  Albany Medical Center, Albany, NY  Uploaded by PainLiveTV  https://www.youtube.com/watch?v=oxJY8qyaUfU
20. Aristidis Veves, MD, Miroslav Backonja, MD, Rayaz A. Malik, MB, PhD.  Painful Diabetic Neuropathy: Epidemiology, Natural History, Early Diagnosis, and Treatment Options; Abstract published in Pain Medicine, Volume 9, Issue 6, September 2008, pages 660-674 https://academic.oup.com/painmedicine/article/9/6/660/1908336#29372939
21. David M. Simpson, MD, John Messina, PharmD, Fang Xie, PhD, Martin Hale, MD.  Fentanyl Buccal Tablet for the Relief of Breakthrough Pain in Opioid-Tolerant Adult Patients with Chronic Neuropathic Pain: A Multicenter, Randomized, Double-blind, Placebo-controlled Study.  Abstract published in Clinical Therapeutics, Volune 29, Issue 4, April 2007, Pages 588-601.  
22. https://www.sciencedirect.com/science/article/abs/pii/S0149291807001075
23. Drugbank.ca Levorphanol 
24. Fudin, Jeffrey PharmD, DAAPM, FASHP, FCCP; Bettinger, Jeffrey PharmD Candidate; and Wegrzyn, Erica BA, BS, PharmD. (2017-04-16 20:14:25) Treatment of Neuropathic Pain.  Pharmacy Times 
25. Howard Kornfeld, MD, FASAM; Heidi Reetz, MD.  Transdermal Buprenorphine, Opioid Rotation to Sublingual Buprenorphine, and the Avoidance of Precipitated Withdrawal; Abstract published in American Journal of Therapeutics: May/June 2015, Volune 22, Issue 3, pp 199-205.
26. Ian Gilron, C. Peter N. Watson, Catherine M. Cahill and Dwight E. Moulin.  Neuropathic pain: a practical guide for the clinician. Abstract published in CMAJ, 2006 Aug 1; 175 (3); 265-275.   
27. Katherine E. Galluzzi.  Management of Neuropathic Pain; Abstract published in The Journal of the American Osteopathic Association, September 2005 Vol. 105, S12-S19. 
28. Kristen E. Zorn, PharmD and Jeffrey Fudin, BS, PharmD, FCCP.  Treatment of Neuropathic Pain: The Role of Unique Opioid Agents; Article published in Practical Pain Management, May 2011.
29. Mamchur, Steve, BSP (2018 November 21) Topicals & Supplements for Neuropathy.  Calgary Neuropathy Association guest speaker handout. 
30. Mayo Clinic Drugs & Supplements-Levorphanol  
31. Myhealth Alberta Health Services-Levorphanol
32. Pain Medicine, Journal  Pain Med. 2019 June 20 (Suppl 1): S2–S12. Published online 2019 Jun 1. doi: 10.1093/pm/pnz075
33. Paul L.I. Dellemijn MD, Hans van Duijn MD, Jan A.L. Vanneste MD, PhD.  Prolonged Treatment with Transdermal Fentanyl in Neuropathic Pain; Abstract published in Journal of Pain and Symptom Management, Volume 16, Issue 4, October 1998, Pages 220-229. 
34. Stanley L. Wiener, MD.  Topical Capsaicin Relieved Painful Diabetic Neuropathy. Article on ACP Journal Club, March 1992 

Thanks to the efforts of both Sylvia Donley and Louise Jones whose best effort were necessary to provide the above technical information in a simplified, clear manner for the novice reader.