Clinical practice recommendations for the management of calciphylaxis associated pain
Pain caused by calciphylaxis is nociceptive, neuropathic and inflammatory in nature as it is a result of metastatic microcalcification and tissue necrosis (16). Choice of analgesia in patients with calciphylaxis is further complicated by ESRD and renal replacement therapy. The authors are not aware of any published guidance on pain management in this group. Therefore, the following guidance extrapolates from first principles and existing literature pertaining to the management of pain in patients with severe and end stage renal impairment but taking into account the unique challenge that calciphylaxis presents in terms of the severity of the pain as described by the physicians surveyed in this paper and the potential for opioid toxicity described by survey respondents as well as the expert opinion of the authors who are palliative medicine physicians (one working in renal palliative care) and renal physicians (one with an expertise in calciphylaxis).
The authors suggest the following pragmatic approach in this population.
- Always refer to either the local palliative medicine team and / or pain team when calciphylaxis is suspected. This is because it is often a diagnosis of exclusion and pain control is difficult in this group and needs a specialist approach from the outset because of the additional morbidity associated with the use of inappropriate analgesia.
- Tissue viability service/wound care specialist referral is essential and daily serial medical photography with consent is advised.
- Ideally admit the patient to a renal unit or to a hospice for symptom control
- Where the patient has capacity, start advance care planning conversations. If the patient does not have capacity and that capacity cannot be enabled, start planning care using the principles of best interests. This is because of the high mortality associated with this condition. It is important to discuss the considerable risk of dying and poor prognosis with the patient and their family.
- Consider enrolment in a clinical trial.
Background pain control
If the patient is opioid naïve, commence a safe opioid at the lowest effective dose (select an opioid that does not have clinically relevant active metabolites that depend on renal excretion) and titrate to effect. The authors recognise that opioids are not considered appropriate for chronic pain. However, this is an acute pain arising in response to tissue injury and death (17) and therefore, we recommend an opioid as first line therapy.
In opioid naïve patients who are starting an opioid for the first time a starting dose of alfentanil 0.5mg continuous subcutaneous infusion (CSCI) over 24 hours is proposed. This is approximately equivalent to morphine 7.5mg/24 hours by subcutaneous infusion. The authors recommend alfentanil as it is not removed by dialysis, it does not cause toxicity in an ESRD population and it occupies a low volume in syringe drivers. This guidance is drawn from literature on the use of opioids in cancer patients with severe and end stage terminal illness (18–20) and is supported by the clinical pharmacology literature (17). Fentanyl by CSCI is an alternative.
Where the patient is not opioid naïve, convert their existing opioid to alfentanil by CSCI. Palliative Medicine can help with conversions if this is outside of the usual scope of practice of the clinician. Titrate daily to either pain relief or toxicity. Increases in background analgesia are usually of the order of 30 – 50% every 24 hours having checked for any signs or symptoms of opioid neurotoxicity. Symptoms of neurotoxicity include troublesome confusion or cognitive slowing, misperceptions or visual hallucinations. If neurotoxicity occurs reduce the dose of opioids by 30% and add adjuvant analgesics e.g. gabapentinoid.
Thirty percentage of patients will experience nausea for 3 – 5 days on starting an opioid. Ensure that an antiemetic is available for use as and when needed e.g. metoclopramide 10mg per oral (PO) or subcutaneously (SC) three times a day. Patients will experience constipation and need to be prescribed a regular daily laxative. Senna 7.5mg twice a day is recommended as a starting dose.
Avoid morphine, oxycodone, tramadol or codeine as background analgesia as they can rarely be titrated to effect in this population without opioid-induced neurotoxicity. Once pain is stable transdermal fentanyl or buprenorphine may be used in place of opioids by continuous subcutaneous infusion. If the lesions heal and pain resolves it is important to reduce the opioids step by step and aim to withdraw them fully.
To address the neuropathic element of pain secondary to calciphylaxis, gabapentin 100mg after each haemodialysis session or pregabalin 25mg after each haemodialysis session may be used in conjunction with opioids. If the patient is not on haemodialysis, start with a dose of 100mg of gabapentin on alternate days or 25mg of pregabalin on alternate days. Caution is needed as gabapentinoids accumulate in ESRD though they are removed by dialysis (21,22)
Discuss the use of a non-steroidal anti-inflammatory drug (NSAID) with the nephrology team as they are very effective for the management of the inflammatory aspect of pain secondary to calciphylaxis. If residual renal function is not important, use an oral or parenteral NSAID (e.g. ketorolac) by continuous subcutaneous infusion for pain that is not controlled with the measures outlined above. Cover with a proton pump inhibitor is recommended. In general, NSAIDs are best used at the minimally effective dose and for a short duration but their harms are weighed against their opioid sparing effect (23)
If background pain remains problematic or dose-limiting toxicity is encountered, consider the addition of methadone as a co-analgesic or rotation to methadone from the current opioid. This step may require hospice inpatient care and should only be undertaken with specialist palliative care guidance.
Breakthrough pain control
Even when background pain control is achieved, the patient may continue to experience spontaneous breakthrough pain. Oxycodone 1-2mg may be used by oral or by subcutaneous injection on a four hourly to 6 hourly basis. In countries where hydromorphone is available, 0.5mg of hydromorphone sublingually four hourly is useful.
Procedure related pain control (during dressing changes and incident volitional breakthrough pain e.g. walking)
Short-acting transmucosal fentanyl preparations have a quick onset and offset of action, which makes them a potentially useful option for dressing changes in patients with calciphylaxis. However, in the UK they are licenced for breakthrough cancer pain and contra-indicated in patients who are opioid naïve. They should be used with caution and with careful patient selection and under the guidance of local pain or palliative medicine teams. An alternative to transmucosal fentanyl, is subcutaneous fentanyl or alfentanil, which have short duration of action. There is a mismatch between the time-action relationship of oral opioids and the time course of breakthrough pain such as that precipitated by dressing changes – the patient may be sleepy for some hours after the procedure.
For dressing changes, use a stepwise approach as follows:
Step1. Short-acting fentanyl preparation (these are available in nasal, sublingual and buccal formulations and it is important to follow the manufacturer’s guidance).
Step 2. SC fentanyl or alfentanil (short duration of action)
Step 3. SC opioid and sedation with subcutaneous midazolam
Step 4. Anaesthesia with propofol and fentanyl under anaesthetic supervision in theatre
The use of a pain tool to record patient reported outcome measures is recommended. The integrated palliative care outcome scale (IPOS) renal is a useful tool though not validated for use in calciphylaxis.