Drug Delivery for Pain Management in Oncology

Why do we change the route or method of administration?

• Need different drug exposure profiles for:

  • need to have quicker onset for breakthrough pain

  • need sustained blood levels for chronic pain

  • to change formation of metabolites

• To avoid first pass

• to have efficient non-invasive delivery

• Patient Factors

  • convenience

  • age

  • dexterity

  • support

Oral opioid products

IR for acute pain/breakthrough pain in cancer - doses every 2-6h

SR/CR/PR for chronic pain

• carefully introduced as the patient has probably already been receiving opioids and developed some kind of tolerance

• given 1-2x a day

• provides more stable blood levels

• must closely follow PIL

• larger doses per unit are more prone to abuse

Principles of dosing

• better to schedule medicaiton dosing rather than waiting for onset of pain

• short acting (IR) = every 4h → takes ~ 1 day for Css

• long acting (CR/PR) = every 12h → takes ~2-4 days for Css

ADFs of Opioids

Abuse-deterrent formulations

• to reduce overdosing and black market supply, there is a focus on promoting tamper-resistant or abuse deterrent formulations

• aims to render the opioids unusable if they attempt to extract the drug

ADF strategies

Abuser wants a a high Cmax in a short Tmax to get the euphoria which makes IR formulations the best option for them

So we can stop it by making it hard to extract the drug from the delivery system

• physical barrier for tablets

  • highly viscous/semisolid layer

  • solids become viscous/gelatinous upon adding water or alcohol when attempting to extract

• aversion to oral formulations

  • include something that if you try to extract the drug, you extract that excipient too which is unpleasant e.g. niacin to deter oral abuse

Transdermal Fentanyl

an analgesic with a very narrow therapeutic index

• used for post-op pain/chronic pain

• reservoir system at first but once the alcohol left, most of the fentanyl remained in patch but wouldn’t leave. This lead to addicts taking the used patches and using alcohol to extract remaining drug

• switched to matrix systems that use up 70% of drug content minimum

• very potent with 1st pass so not good for oral

• 1-2ng/mL provides effective Cp

• Once alcohol leaves the reservoir, some drug can be

Transdermal Buprenorphine

• partial agonist and antagonist action

• 0 oral BA

• short t1/2

How can patches be abused?

• chewed to release 3 day dose for mucosal delivery

• multiple patches on skin

• gel removed and boiled to extract drug which is either injected or drunk

Breakthrough Cancer Pain

Transient increase in pain in a cancer patient who has stable persistent pain treated with opioids

Impact of Breakthrough pain

• depression

• anxiety

• functional impairment

• background pain

Treating Breakthrough Pain

• deal with it ASAP - don’t wait it out

• drugs include

  • morphine

  • oxycodone

  • fentanyl

  • hydromorphone

• Fentanyl is good cause of the variety of IR forms:

  • lozenge - sublingual (under tongue)

  • buccal/sublingual tablet

  • nasal spray

Charactersitics of Fentanyl Citrate

• potent m-opioid analgesic with rapid onset of analgesia

• most lipophillic of the clinically available opioids

• quickly crosses over cellular barriers and provides broad tissue distribution

• oral transmucosal fentanyl citrate is the first rapid onset opioid to be approved for treating breakthrough cancer pain

Buccal/Sublingual administration

• convenient and easy to use

• advantages:

  • large SA

  • high permeability

  • high vascularity

  • uniform temp

  • high BA due to avoidance of 1st pass