Medication treatment of pain in EB: how to choose

Kenneth R. Goldschneider, M.D.

Cincinnati Children’s Hospital Cincinnati Ohio, USA

Disclosures

• No conflicts of interest

Objectives

• Understand the strengths and weaknesses of basic analgesics as used for EB

• Be aware of the basic differences among the classes of medications used for pain and itching in EB

• Know a few questions that can help to guide which medicine to use for pain or itch

Umm….?

Classes of Pain Medications Commonly used for Pain in EB

• Opioids

• Nonsteroidal anti-inflammatory drugs (NSAIDs) and Acetaminophen

• Ketamine

• Neuropathic medications

– E.g. gabapentin, amitriptyline

Opioids

PROS

• Many routes

• Effective

• Many formulations

• No Ceiling Effect

CONS

• Side effects

• Social Stigma

• Variable availability

• Abuse potential

Theory: mu, kappa and delta opioid receptor mediate pain transmission Blockade of these receptor reduces pain of many types

Opioids: Routes and Formulations

Intravenous

Oral

Sublingual

Epidural

Intrathecal

Transbuccal

Transdermal

Subcutaneous

Intranasal

Rectal

Transpulmonary

Ceiling Effect

• A point beyond which increasing the dose will result in no further effect

0

1

2

3

4

5

6

DOSE

Ceiling Effect

DOSE

Opioids

NSAIDs

Opioid Side Effects

Important in EB

• Constipation

• Itching

Less important in EB

• Sedation

• Respiratory depression

• Nausea

• Mental clouding

Opioids: other considerations

Social stigma/abuse potential

• Leads to fear of use

• Leads to fear of prescribing

• Is a rare problem

• Opioids are a tool to do a job, no more and no less

Variable availability

• Opioids will vary in how easily they can be obtained depending on local law, regulation, manufacturing and prescribing patterns

Codeine

• Bad

• Yuck

• Phooey

• Ick

• Dangerous to some

• Ineffective for others

• Use something else unless the patient has a good history with it.

Opioids: how to choose

• What has worked before?

• What side effects have been experienced?

• What is the context?

– Is long-acting or short-acting needed?

• Avoid codeine unless the patient prefers it

– KRG preference

NSAIDs (nonsteroidal anti-inflammatory drugs)

PROS

Effective

Anti-inflammatory

Available

Several routes

Not sedating or respiratory depressant

Non-constipating

CONS

• Side effects

• Ceiling effect

Theory: Cyclooxegenases are key mediators of peripheral pain and inflammation NSAIDs block cycolooxygenase

NSAID Side Effects

Important in EB

• Increased bleeding risk

Less important in EB

• Kidney toxicity

• Liver toxicity

• GI effects

– Ulceration, reflux

Acetaminophen

PROS

• Effective for mild pain

• Availability

• Oral, rectal, Intravenous

CONS

• Cumulative toxicity risk

– Hidden exposures

Theory: It does something in the central nervous system, probably. Anyhow, it works.

www.addictionsearch.com/treatment_articles www.fda.gov/ForConsumers/ConsumerUpdates/ucm2 63989.htm www.canada.com/health/Study+links+acetaminophen +with+higher+risk+teenage+asthma/3394455/story.html

NSAIDs: how to choose

• Is the pain related to inflammation, bones or muscles?

• What are the ongoing bleeding issues?

• Are there any kidney problems?

• What other sources of acetaminophen are there?

Ketamine

PROS

• Effective

• Oral or intravenous

• Little respiratory effect

CONS

• Availability

• Regulations

• Side effects

• Bitter taste

Theory: Many receptors are involved in pain (e.g. AMPS, NMDA, opioid, 5-HT, adrenergic) Ketamine hits them all

Ketamine: how to choose

• Qualified personnel to administer it?

• Local regulations permit?

• Is there a place to test dose it?

Neuropathic Medications

• Anticonvulsants

– E.g. gabapentin, oxcarbazepine, carbamazepine

• Tricyclic antidepressants

– E.g. amitriptyline, doxepin, nortriptyline

• Newer antidepressants

– E.g. Duloxetine

Neuropathic Medications

PROS

• Helpful for some pain

• Helpful for some itching

• No tolerance

• No respiratory depression

• Some can help with sleep

CONS

• Less experience for general practitioners

• Potential interactions – Especially tricyclic

antidepressants

• Choices not always clear

Theory: Many chronic pain conditions involve overexcited nerves. Quieting those nerve can reduce pain

Neuropathic medications: how to choose

• Practitioner experienced with these medications?

• Is the pain related to nerves?

• Has the pain been poorly responsive to other treatments?

• Heart or kidney problems?

• Pain interfering with sleep?

• What other medications is the patient taking?

Drug Treatment of Itching

• Antihistamines – Sedating or non-sedating

• Change opioids – if that is a factor

• Ondansetron?

• Gabapentin?

• Doxepin or other tricyclic antidepressants?

• Mirtazepine?

Antihistamines

PROS

• Classic treatment for itch

• Effective for histamine mediated itching

• Low toxicity

CONS

• Role of histamine unclear in EB

• Variable effectiveness

Theory: histamine is a key mediator of itching Itch receptors respond to histamine, but not other painful stimuli

Opioid Rotation

PROS

• Opioids very in their itch – inducing properties

• Changing opioids is usually easy to do

• Little downside

• A common technique for general opioid side effect management

CONS

• No guarantee that the next opioid will be better

• Hence, trial and error

• May trade one side effect for another

• Limitations in medication or usable formulation

Theory: opioids cause itching; opioids overlap incompletely. Change from one to another to reduce dosing and side effects

Ondansetron

PROS

• Low toxicity

• Comes in dissolvable tablets

CONS

• Expensive

• Efficacy unclear

Theory: Serotonin is involved in itch Ondansetron is an 5-HT3 inhibitor

Gabapentin

PROS

• Low toxicity

• Comes as liquid

• No drug interactions

• Works in post-burn itching

CONS

• Side effects – Mood swings, sedation

• Variable success

Theory: itch transmitted via c-fibers, similar to pain Gabapentin is useful in neuropathic pain

Doxepin/Amitriptyline

PROS

• Combination antihistamine and neuropathic mechanisms

• Helps with sleep, if that is a problem

• Once a day dosing (bedtime)

CONS

• Low toxicity threshold

• Numerous drug interactions

• Variable response

• Potential prolonged QT issues, obtaining ECG not easy in EB

Theory: histamine and serotonin are involved in itch Block both and itch will be less

Mirtazapine

PROS

• Helpful in other types of itching

• Helps with sleep

CONS

• Little experience in EB – Dosing in kids?

Theory: Anti-H1, anti 5-HT and anti-noradrenaline Has helped in lymphoma and uremia related itch

Itch treatment: how to choose

• Did itch change with the new medication or treatment?

• Is the itch interfering with sleep?

• What other medications is the patient taking?

• Are there any heart or kidney problems?

• What has been tried before?

• Remember: non-medication treatments should always be used also

Conclusion

• Many pain medications and anti-itch medications are available

• The effectiveness of many of them has not been shown, or is variable

• Most commonly, medications are used in combination

• Best practice care guidelines for pain are being developed (almost done!) – The level of evidence is low – Research in this area is imperative

You are the Champions, my friends… Thank you