What are the recommendations for using codeine in patients with Van Wilderan's (Von Willebrand) disorder?

Codeine Use in Von Willebrand Disease

Codeine should be avoided in patients with Von Willebrand Disease (VWD) due to increased bleeding risk and lack of specific safety data in this population. 1

Understanding Von Willebrand Disease and Bleeding Risk

Von Willebrand Disease is the most common inherited bleeding disorder characterized by:

• Deficiency or abnormal activity of von Willebrand factor (VWF), a multi-adhesive protein that binds platelets to exposed subendothelium and carries factor VIII in circulation 2
• Clinical symptoms typically include mucous membrane bleeding, soft tissue bleeding, and bleeding after surgery 2
• Three main types exist:
  • Type 1: Partial quantitative VWF deficiency 2
  • Type 2: Qualitative VWF abnormalities 2
  • Type 3: Severe quantitative VWF deficiency 2

Why Codeine Should Be Avoided in VWD

Bleeding Risk Considerations

• Patients with VWD already have an increased bleeding risk, particularly affecting mucous membranes 2, 3
• Codeine and other opioids may mask symptoms of bleeding, potentially delaying recognition of hemorrhagic complications 1
• In cases of bleeding diathesis in VWD patients, screening for acquired von Willebrand disease should be performed before considering any medication that might affect hemostasis 1

Pharmacogenetic Concerns

• Codeine is a prodrug that requires conversion to morphine by the CYP2D6 enzyme for analgesic effect 4
• Genetic polymorphisms in CYP2D6 create unpredictable pharmacokinetics:
  • Poor metabolizers experience little pain relief 4
  • Ultrarapid metabolizers have increased risk of morphine toxicity 4
• This unpredictability is particularly problematic in patients with underlying bleeding disorders 5

Alternative Pain Management Options for VWD Patients

Non-Opioid Analgesics

• Acetaminophen (paracetamol) is generally considered safe for mild pain in VWD patients 5
• NSAIDs should be avoided due to their antiplatelet effects, which can further increase bleeding risk 5, 2

Treatment of VWD to Prevent Bleeding

• Desmopressin (DDAVP) is effective for many Type 1 VWD patients with factor levels ≥10 U/dL 2, 6

  • Promotes release of VWF and factor VIII from storage sites 6
  • Can be used prophylactically before procedures or to treat acute bleeding 6

• VWF-containing concentrates are indicated when:

  • Desmopressin is ineffective (mainly in Type 2 and 3 VWD) 2
  • Correction is required for extended periods (e.g., major surgery) 2, 6
  • For urgent bleeding management in severe cases 6

• Antifibrinolytics (e.g., tranexamic acid) can be effective for mucosal bleeding 3

Special Considerations

• Monitoring of individual response to desmopressin in the non-bleeding state is recommended to determine expected response during bleeding episodes 6
• For patients requiring pain management, consultation with a hematologist is advised before prescribing any analgesics 1
• In cases of acquired von Willebrand syndrome during extracorporeal membrane oxygenation (ECMO), plasma-derived VWF concentrate may be considered for bleeding management 1

Clinical Approach to Pain Management in VWD

1. Assess severity of pain and bleeding risk based on VWD type 2, 3
2. For mild pain: use acetaminophen as first-line therapy 5
3. For moderate to severe pain: consider non-opioid alternatives and consult hematology 5, 3
4. Treat underlying VWD with appropriate therapy (desmopressin or VWF concentrates) 2, 6
5. Monitor closely for signs of bleeding if any analgesic is administered 1, 6