Pain - Neuropathic

Overview

Patients with chronic disease may experience pain from a variety of causes. They might have nociceptive (somatic: soft tissue, bone, joints (dull/aching); or visceral: “cramping/gnawing”) pain and/or neuropathic (nerve damage or aberrant somatosensory processing: “burning/electrical”) pain. Neuropathic pain arises from structural or functional derangement of the tissues of the nervous system itself. Adjectives like burning or electrical may indicate neuropathic pain. True neuropathic pain is uncommon.

Unmanaged or unrelieved pain has a significant impact on the overall wellbeing of patients and their caregivers. This may lead to significant morbidity, such as falls, agitation and mood disorders. There are multiple factors that influence pain, including emotional, psychological, spiritual, social and other domains of personhood. Often, an interdisciplinary approach is necessary to effectively manage chronic pain in the palliative care setting.

When managing pain, it is important to determine if the pain is acute versus chronic. These guidelines are for chronic neuropathic pain (e.g. pain that is present for >3 months)

Step 1 Consider the Underlying Causes of Neuropathic Pain

Is the pain chronic (present for >3 months). Consider the differential diagnosis. Modify what is modifiable if this is in keeping with the patient’s goals of care
Is the pain acute with an identifiable non-disease or disease-related acute cause that can be treated (e.g. a hip fracture after a fall, spontaneous bacterial peritonitis, increasing ascites contributing to abdominal distension). Treat the cause

Step 2 Non-Pharmacological Management of Neuropathic Pain

General Principles

Non-pharmacological measures should be considered in all patients where the symptom is having a significant impact on quality of life or ability to function
Pain is a complex multidimensional experience with biopsychosocial inputs. Depending upon the situation, assess the following three things as part of a thorough pain assessment:

Determine the severity of the pain and its impact using a standardized pain assessment tool
- Investigate based on patient’s goals of care
- Use the information from the assessment to determine the etiology of the pain and treat accordingly
Consider psychosocial or spiritual contributors to pain and look for co-existing mental health conditions as these will affect the pain experience:
- Depression/anxiety
- Others (e.g. post-traumatic stress disorder, psychosis)
Complete a risk assessment: Ask about alcohol and other substance use as this may affect your management decisions

To monitor the effectiveness of pain management, reassess the pain regularly and frequently (at least monthly)
Provide patients with the Pain Patient Handout

Complimentary Treatments

OT/PT assessment for safe mobilizing, splinting, supports and pressure reducing equipment
Cognitive behavioral therapy, hypnosis, relaxation, guided imagery
Complementary alternative management, such as massage, acupuncture, acupressure, electrical stimulation
Exercise gentle movement such as tai chi or tone and strengthening
Heat and cold applications
Relevant spiritual and cultural practices

Step 3 Pharmacological Management of Neuropathic Pain

General Principles

The primary goal of therapy is to balance symptom control with the careful protection of physical function and cognition. Consider pharmacological therapy when the symptoms persist after trialing non-pharmacological interventions
It is important to consider the type of pain the patient is experiencing – main consideration: Nociceptive (somatic/visceral pain) versus Neuropathic (nervous system pain, “burning/electrical”)
- Choose adjuvant medications based on the type of pain
Treatment choices are also guided by severity or pain intensity (mild, moderate, or severe) on a 0-10 scale, 0 being no pain and 10 being the worst possible. When pain is expected to worsen, however, choosing from options for more intense pain and starting at lower doses may avoid a future medication switch
Integrate non-pharmacological treatments and analgesics (see below) for all levels of pain: mild, moderate or severe
REASSESS PAIN AT LEAST MONTHLY – us the PEG, ESAS-r or the Follow-up Pain Assessment Tool to determine if there is benefit to current medication and follow these steps:
- If the pain is not responding as expected, go back to your differential diagnosis, re-assess for non-physical contributors to pain and review expectations for pain relief
- Pain adequately controlled – Continue to reassess monthly
- Pain somewhat controlled but inadequate:
  1. Titrate up first-line medication as tolerated
  2. If unable to tolerate increase in dose of first-line medication, i.e. due to side-effects - or maximum recommended dose achieved, then add second line medication
- Pain not controlled (no benefit):
  1. Titrate up medication as tolerated
  2. If still no benefit with dose increase, or limited benefit but significant intolerable side-effects, then discontinue and trial second-line medication
The dose of medications may need to be adjusted with deteriorating liver function

1. Start with Adjuvant Therapy

General Principles

If non-pharmacological interventions are ineffective start with Adjuvant Therapy

Gabapentin First-line Agent

For neuropathic pain: Initiate treatment at 300 mg orally per day and gradually titrate dose if needed over weeks due to delayed onset of action and to improve tolerability
Maximum dose: 3600 mg/day in divided doses

Pregabalin First-line Agent

Starting dose 75 mg orally twice a day. Titrate to tolerance and effect every 1 to 3 weeks
Maximum dose: 600 mg in divided doses 2-3 times per day

Carbamazepine Second-line Agent

Starting dose: 200 mg/day, gradually increasing over several weeks in increments of 200 mg/day as needed. Usual maintenance dose: 600 to 800 mg/day
Maximum dose: 1.2 g/day

Elderly are more susceptible to carbamazepine-induced confusion and agitation, AV block, bradycardia, and syndrome of inappropriate antidiuretic hormone (SIADH)

Amitriptyline Second-line Agent

Starting dose 25 mg orally daily. People who are smaller or frail may be started at 10 mg. Titrate slowly every 1-2 weeks
Maximum dose: 100 mg daily

Doxepin Second-line Agent

Starting dose 3 to 6 mg once daily within 30 minutes of bedtime
Maximum dose: 6 mg/day

Avoid abrupt discontinuation

Carbamazepine

Contraindicated in patients with severe liver disease or heart failure

Doxepin

Contraindicated in patients with severe liver disease or heart failure

If pain persists add a non-opioid +/- adjuvant therapy

2. Non-Opioid Therapy

General Principles

If non-opioid therapies are ineffective and pain is significantly impacting quality of life and function, weigh the risks and benefits of opioid therapy
Reassess at least monthly using the Follow-Up Pain Assessment Tool

Acetaminophen First-line Agent

Acetaminophen is generally well tolerated in patients with CLD or cirrhosis who do not consume alcohol, provided the total daily dose is limited to no more than 2 g/day

Diclofenac Gel First-line Agent

5% - 10% gel applied topically two or three times daily. Over the counter products are 1.16% and 2.23%

Topical Compounded Products First-line Agent

For example: Gabapentin 6% / Ketoprofen 10% / Lidocaine 5% / Cyclobenzaprine 2%

Various combinations exist where concentration can be manipulated for patient preference

Acetaminophen

Contraindicated in patients with severe liver disease

If pain persists consider adding an opioid, +/- adjuvant, +/- non-opioid

3. Opioid Therapy

General Principles

If adjuvant and non-opioid therapies are ineffective and pain is significantly impacting quality of life AND function, weigh the risks and benefits of opioid therapy
Consider completing an opioid risk tool and order a bowel routine (see Constipation Guideline). Start with low doses and titrate slowly to effect
Certain opioid therapy, e.g. Fentanyl Transdermal Patch, should not be used in opioid naive patients and should be considered for those relatively stable on their oral dosing prior to switching
Option to continue with non-opioid therapy
Opioids are contraindicated in patients with acute or bronchial asthma and gastrointestinal obstruction including paralytic ileus
Risk of respiratory and CNS depression. All opioids should be used with caution in patients with COPD due to the potential for respiratory depression and worsening hypercapnia. Also use with caution in patients with a history of seizure disorder, chronic constipation, and kidney/liver disease
Reassess at least monthly using the Follow-Up Pain Assessment Tool. Monitor for signs of toxicity, including sedation and respiratory depression

Opioid Considerations

The risks and benefits of opioid medications need to be very carefully weighed in all patients, but particularly in those patients with cirrhosis. Follow the individualized protocol when switching, tapering or discontinuing the opioids where indicated, to avoid withdrawal/discontinuation symptoms.

REASSESS PAIN AT LEAST MONTHLY - If non-opioid therapies are ineffective and pain is significantly impacting quality of life AND function, weigh the risks and benefits of opioid therapy
Consider opioids only in patients who have failed non-opioid therapies and have refractory pain that is significantly impacting quality of life and function
Complete an Opioid Risk Assessment (Opioid Risk Tool)
Unless the practitioner is very experienced, assistance should be sought before using opioids in the following situations:
- Contributing psychosocial determinants or untreated mental health disorders
- High addiction risk (Opioid risk tool)
- Uncontrolled hepatic encephalopathy (see CCAB HE page)

Patients meeting these criteria often benefit from consultation with an inter-disciplinary Pain Clinic (earlier stages of cirrhosis), palliative care (end-of-life), hepatology (uncontrolled hepatic encephalopathy)
If clinic wait lists are too long or rapid assistance is required, in Alberta, these specialists can be reached through RAAPID North (780-735-0811) or RAAPID South (403-944-4486).
Click here for instructions on getting a telephone consultation at the University of Alberta Pain Medicine clinic

Initiating Opioid Therapy

Review the results of the opioid risk tool
Educate the patient about expected side effects
Review the patient’s Personal Pain Goal (numerical pain intensity they can function in the capacity they are best able, see general approach to symptom assessment box at top of page), in addition to goals for increased function and quality of life. Reinforce that in a best-case scenario, pain typically decreases by 30-50%
Administration should be regarded as a therapeutic trial, with improved quality of life and function (not merely reduced pain intensity) as the goal. Explain this to the patient prior to starting the opioid
Start low – start with low doses, especially with impaired renal or liver function and in the elderly
Go slow – titrate doses gradually to analgesic response or until patient experiences unacceptable side effects (side-effect ceiling)
Oral Route is preferred. Oral route is the most common, safest and least invasive route of administration. Other routes can be used if needed, such as subcutaneous, intravenous, rectal, transdermal, sublingual, buccal or transmucosal
Have a regular fixed administration schedule around the clock. For constant chronic pain, a fixed regular dosing schedule (i.e. every 4 hours), is recommended
All opioids are associated with a risk of constipation and, for cirrhosis patients, worsening hepatic encephalopathy
Plan for adverse effects (e.g. constipation, nausea). Start laxatives proactively, order a bowel routine (see: Constipation Guideline), and for the first 3-5 days of therapy (or dose changes), order prn anti-nauseants (See: Nausea Guideline)
In physically or cognitively frail patients, some experts start with a single dose of an opioid at qhs to assess tolerance, and to add doses from there
Consider Home Care involvement if the patient has difficulty managing their own medication
AVOID using codeine:
- Unpredictable safety and efficacy due to variable liver metabolism among individuals
- Possible interactions with other medications causing variable metabolism
- It is often not sufficient for cancer pain and as intensity increased, a switch to a strong opioid will need to be made
Do not initiate long-acting formulations in patients with cirrhosis or advanced kidney failure

Opioid Titration

Considerations for Opioid Titration: (Opioid Conversion Table)

Ongoing pain re-assessment is critical
Titrate analgesics every 3-7 days as needed and tolerated. Slower titration may be required
Titrating up the regular Opioid dose:

Add the total amount of opioid used in the last 24 hours (regular and breakthrough doses). Divide the total dose by 6, and prescribe this amount every 4 hours (q4H)

For ongoing pain exceeding patients pain control targets, adjust as follows:
- - For pain rated 3-6, increase dose of opioid by 25%
  - For pain rated 7-10, increase dose of opioid by 50%

Breakthrough (PRN) dose prescription: 10% of total 24 hour opioid dose every 1-2 hrs PRN
If the patient is also taking benzodiazepines, consider titrating down the dose, while opioids are being increased. If not, titrate opioids more slowly

Hydromorphone First-line Agent

Begin hydromorphone(immediate release) 0.5 – 1 mg po or 0.2 – 0.5 mg sc q4h
PRN dose can be equal to or half of the q4h dose.

Fentanyl Transdermal Patch First-line Agent

Not recommended in opioid naive patients. Its intention is for titration. Starting dose of 12 mcg/h every 72 hours is ~ 30 mg morphine oral equivalent per day (see opioid conversion table)

A patient needs to have been on morphine 60 mg daily oral equivalent for at least 10-14 days to no longer be considered "opioid naive"

Morphine (immediate release) First-line Agent

Starting dose 2.5 mg orally every 4 or 6 hours. Titrate to a dose that provides adequate analgesia and minimizes adverse reactions
Reduce dose and frequency by approximately 50% in advanced CLD or cirrhosis
Titrate dose gradually to avoid accumulation of active drug

Buprenorphine First-line Agent

Starting dose: transdermal patch 5 mcg/h every 7days

Buprenorphine transdermal patch is not indicated as an as-needed (prn) analgesic
It should not be used in individuals less than 40 kg in weight because of altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance.
The patch should be worn for 7 days continuously before changing to a new patch at the same dose. A new skin area should be selected when changing to a new patch. After the patch is removed, a 3-week interval is required before the same area can be re-used.
No change in dose titration is required in patients with renal impairment or mild to moderate hepatic impairment.

Oxycodone Second-line Agent

Starting dose (immediate release): 5 mg every 8 hours. Titrate gradually based on patient response and adverse effects

Methadone Second-line Agent

Starting dose 2.5 mg orally every 12 hours. Titrate to a dose that provides adequate analgesia and minimizes adverse reactions. Can increase frequency to every 8 hours. Dose titration should occur no more than once per week

Methadone is used for around-the-clock treatment of severe pain. This medicine is not for use on an as-needed basis for pain
Monitor for signs of toxicity including sedation and respiratory depression
Best used by practitioners experienced with methadone use. Primary care can maintain and refill methadone if a specialist has established an effective dose
If you are looking to refresh or improve your knowledge on methadone for analgesia, please visit Virtual Hospice - the Learning Hub and click on Methadone4Pain