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Friday 24 May 2019
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Managing pain in renal impairment

PRACTICAL THERAPEUTICS
The article discusses the importance of pain assessment to identify the cause and impact of pain and pharmacological pain management strategies in the context of chronic kidney disease
Alison Dwyer RGN MSc
Consultant Nurse in Pain Management, Manchester and Salford Pain Centre; Honorary Lecturer, Salford University 
Janet Whittam BPharm MRPharmS
Senior Clinical Pharmacist 
Salford Royal NHS Foundation Trust, Manchester, UK
Email: Alison.Dwyer@srft.nhs.uk
Pain is the most common symptom reported by patients with chronic kidney disease (CKD) (>70% of patients).(1) It is associated with reduced quality of life, increased anxiety, depression and sleep disturbance.(2) The impact of chronic pain in CKD has been associated with adverse affects on quality of life(3) and even reduced life expectancy.(4) 
Pain is under-reported and often poorly assessed or recognised by healthcare professionals.(4) Management is further hindered by complex pharmacology and pharmacokinetics, with delayed drug clearance, dialysis effects and toxicity. Lack of understanding can lead to prescribing being avoided for fear of getting it wrong. In addition, side effects of analgesia may mimic uraemic symptoms, leading to inappropriate withdrawal of treatment. 
A complex phenomenon
Pain is a complex phenomenon with physiological, emotional and behavioural components contributing to the pain experience. Nociception involves the stimulation of nerves that convey information about potential tissue damage to the brain. Pain is more than nociception alone. It is the subjective perception that results from the transduction, transmission and modulation of this sensory information (Box 1). 
This input may be filtered through an individual's genetic composition, prior learning history, current psychological status and sociocultural influences.(5) The International Association for the Study of Pain (IASP) has described pain as: ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage and expressed in terms of such damage’.(6) Pain is therefore a complex, subjective, multidimensional experience. Nociception, or degree of tissue damage, therefore does not equate to the pain experienced. 
Classification
The classification of pain continues to evolve, although two clear concepts dominate: that of tissue injury pain or ‘inflammatory pain’ or ‘nociceptive pain’ and pain arising from nervous system injury or neuropathic pain. Although simplistic, this approach is commonly accepted by pain specialists. Neuropathic pain has been defined as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory nervous system’.(7) It is best thought of as an abnormal activation of the pain pathways.
It can occur as a result of injury to peripheral nerves (peripheral neuropathic pain) or lesions within the brain or spinal cord (central neuropathic pain). It can be spontaneous or evoked, and often described as shooting, stabbing or burning pain. Common neuropathic chronic pain conditions include painful polyneuropathy, for example, from diabetes or peripheral vascular disease, (common in CKD), postherpetic neuralgia, peripheral nerve injury, radiculopathy, cancer-related pain and central post-stroke pain.(8,9) Contrary to nociceptive pain, which results from physiological activation of nociceptors alerting to potential or actual tissue injury, chronic neuropathic pain has no beneficial effect. 
Pain in CKD
Pain in CKD is often multifactoral, with a mixture of nociceptive and neuropathic pain symptoms. The number and severity of symptoms reported in this patient population is similar to hospitalised patients in a palliative care setting.(10) Pain may result from the primary disease (for example, distended polycystic kidneys) or be related to the management of the renal failure, where complications from central lines and arteriovenous fistulas can lead to painful ischaemic neuropathies.
Most commonly, pain is related to co-morbid illness. As renal impairment is common in patients with diabetes, cardiovascular disease or cancer (from disease or treatment, for example, chemotherapy, obstructive uropathy, myeloma) pain syndromes include, painful ischaemic limbs, painful diabetic neuropathy and bone disease.(1,2,10) Musculoskeletal pain from arthritis in elderly end-stage renal disease (ESRD) reflects the prevalence in the general population. 
In addition, there are numerous painful syndromes unique to ESRD, such as calciphylaxis, nephrogenic systemic fibrosis dialysis-related amyloidosis, and renal osteodystrophy, which may develop during a patient’s time on dialysis (Table 1).(1) 
Purpose of assessment
Assessment of pain is essential in identifying its cause, severity and impact. Most acute pain is nociceptive pain. If a treatable condition is identified, for example, infection (as in pyelonephritis), or trauma, first line management should be to target the cause, although pain- management should not be withheld during the diagnostic phase. Key elements of acute pain assessment include onset/ duration, location, severity and treatment and effect to date. Simple unidimensional pain assessment tools are easily accessible and frequently utilised in hospitals to assess severity of acute pain (verbal report, mild–moderate severe or numerical scale 0–10).
Chronic pain is often more challenging because of the complexity of underlying causes. It often presents with a mixture of nociceptive and neuropathic symptoms and can be resistant to medicine management. Chronic pain is associated with physical decline and the psychosocial burden of long-term illness. In these circumstances, a bio-psychosocial approach to pain assessment is more appropriate to identify type of pain, severity, impact on mood (including anxiety, depression and sleep disturbance) and physical function.(12)  Management must include the outcome of any treatment plan.
Commonly used pain assessment tools can be accessed via the British Pain Society or pain topics web sites (www.britishpainsociety.org; www.pain-topics.org/clinical_concepts/assess.php). 
Where neuropathic pain is suspected, this is often more difficult to diagnose and, again, patients are at risk of under treatment. Pain assessment tools can assist in understanding the severity and impact of pain but they do not allude to the underlying cause of pain or ‘pain generating mechanism’. For neuropathic pain, the LANSS tool has been shown to be clinically effective.(13) It therefore follows that, if the mechanism of pain is not identified, it may not be possible to maximise the benefit from pharmacological pain management.(10,14) If neuropathic pain is suspected, or where patients fail to respond to first-line treatments, they may benefit from referral to specialist services for assessment of their chronic pain.
Pharmacology, pain and CKD
Administration of analgesia in CKD is complicated by decreased renal clearance of drugs and/or their metabolites and in some patients, the effects of dialysis. It should also be remembered that, for many chronic pain syndromes, one form of analgesia is seldom sufficient. 
The World Health Organization (WHO) pain ladder, although originally designed to assist in the pharmacological treatment of malignant pain, is now widely accepted as a step-wise approach to treating pain in the wider population, ensuring in the acute pain situation that the step chosen is at a level suitable for the anticipated level of pain. It has been shown to be useful in ESRD,(15) with minor alternations to the drug choices to take into account the impact of renal impairment. Figure 1 is an adaptation of the WHO ladder that reflects current practice in the management of pain in CKD in our acute hospital setting. Table 2 details analgesic titration.
Step 1
For the treatment of mild pain, paracetamol is a safe and effective choice of therapy. Oral bioavailability is estimated at between 63 and 89%,(16) with an approximate onset of action of 30 minutes. Intravenous paracetamol should be considered for acute pain where a rapid achievement of therapeutic concentration is considered beneficial. A reduction in total daily dose is necessary for those weighing <50kg. 
The use of non-steroidal anti-inflammatory drugs (NSAIDS) and cyclo-oxygenase 2 (COX-2) inhibitors are known to have an adverse effect on renal function. Chronic use is linked to progression of CKD and, in acute situations, can cause a reversible decrease in glomerular filtration rate (GFR). NSAIDs and COX-2 inhibitors should therefore be avoided in acute illness or in impaired renal function. In ESRD, where renal replacement therapy has been initiated, NSAIDS can be administered as in normal renal function if no other contraindications have been identified.
Step 2
Normally reserved for weak opioids with the addition of paracetamol or an adjuvant. The choice in the non-CKD population would usually be codeine and tramadol. It is important to recognise that between 2 and 10% of people lack the isoenzyme CYP450 2D6, necessary for the metabolism of the prodrugs codeine and tramadol to their active form and therefore will receive no analgesic benefit from these drugs.(17)
Codeine is metabolised to the active and renally excreted codeine-6-glucuronide and to morphine (approximately 10%), and therefore should be titrated slowly if used, with single doses not greater than 30mg. Tramadol, which acts as a weak mu-opioid receptor agonist and also by inhibition of the reuptake of noradrenaline and serotonin, is effective for both nociceptive and mild neuropathic pain and can therefore be a useful agent. It is not known to be directly nephrotoxic but it does have an active metabolite, o-demethyl tramadol. Both the parent drug and this metabolite rely upon renal excretion and the half-life of the latter is doubled in advanced CKD. Reduced dose or prolonged time intervals are recommended to reduce side effects. 
Step 3: strong opioids
All the opioids (with the exception of methadone) undergo hepatic metabolism, the metabolites then undergoing high degrees of renal excretion. 
The problem with morphine is that its metabolite, morphine-6-glucuronide, is more potent than the parent compound and it is dependent on renal or dialysis clearance. Doses of morphine effective in patients with normal renal function become toxic as the morphine is metabolised and not cleared. 
Where the oral route is preferred, oxycodone has gained popularity over hydromorphine for its wide dosing range, variety of preparations and ease of conversion and titration. The parent drug is responsible for the analgesic effects with less potent metabolites (oxymorphone) than morphine. Both drug and metabolite are excreted renally, so there remains the potential for accumulation, and starting doses should be low and titrated accordingly. Modified-release oxycontin is suitable for chronic stable pain.
Fentanyl is a synthetic, strong opioid metabolised primarily to norfentanyl, which is inactive (<10% being excreted as unchanged). Although it is considered to be one of the safest opioids in this patient group,(18) it is not available as an oral preparation. Fentanyl is most commonly used as a topical patch for the treatment of chronic stable pain, but is also available for the treatment of acute pain, usually intra-operative and postoperative pain in an intravenous format. Fentanyl has 100-times greater potency than morphine and should only be initiated and titrated by experienced staff. 
Adjuvants for neuropathic pain
In our hospital setting and pain clinic, we have adopted a stepwise approach to the use of anti-neuropathic agents. Tricyclic antidepressants (TCA) have good evidence of efficacy for both central (for example, post-stroke pain) and peripheral (for example, diabetic neuropathy) neuropathic pain syndromes.19 Realistic expectations from any drug therapy for chronic pain would be 30–50% reduction in symptoms and often more than one agent is required. For many patients, the side-effect profile of the TCAs may be unacceptable but, at low doses, amitriptyline is often well tolerated. There are no dose adjustments necessary in CKD; however, amitriptyline should be started at a low dose (usually 10mg given in the evening) and titrated to effect depending on tolerability. Nortriptyline may be a useful substitute if patients have good analgesic effect but titration is limited by sedation. 
If ineffective or poorly tolerated, the next step would be the alpha-2-delta binding agent, gabapentin (use first-line if TCA contraindicated). There is no evidence to demonstrate superior efficacy between gabapentin and pregabalin(17) and both require dosage reduction in the patient with CKD (Figure 2). Gabapentin is, however, more cost effective and is often tolerated well if titrated to effect.
Duloxetine is a serotonin–norepinephrine reuptake inhibitor recommended by the National Institute for Health and Care Excellence for patients with diabetic neuropathy.(20) We often use this second-line to TCAs if the antidepressant benefit is desirable as well as the neuropathic pain effects, or after gabapentin if ineffective. 
Topical agents, such as capsaicin cream or lidocaine plasters, can be considered for localised neuropathic pain where it is desirable to avoid systemic administration of medication, or if oral medications have been poorly tolerated or ineffective.
Complex pain syndromes, such as calciphylaxis or uraemic neuropathy, often present with mixed pain symptoms (nociceptive and neuropathic) and require multimodal analgesic regimens to maximise benefit. For these patients, input from a specialist in pain management is recommended. 
Conclusions
Pain is common in patients with CKD. Assessment is fundamental to successful treatment and pharmacological intervention should be aimed at the underlying ‘pain generator’. Medication needs to be adjusted depending on metabolites and clearance and this can be achieved by using the tools presented. Initial analgesic management requires careful titration of medications to response and this is best achieved using an as required prescription. Analgesia for chronic stable pain should be administered regularly and modified-release preparations are often more effective in avoiding the peaks and troughs of benefits and side effects. If patients fail to respond to first-line medications, or present with complex chronic pain syndromes, input from a specialist in pain management is recommended. 
Resources
www.pain-topics.org/clinical_concepts/assess.php 
www.britishpainsociety.org 
www.paintoolkit.org/
www.medicine.ox.ac.uk/bandolier/booth/painpag/index2.html
www.nice.org.uk/cg73
www.renal.org/home.aspx
References
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  2. Kafkia TM et al. Pain in chronic kidney disease: prevalence, cause and management. J Ren Care 2011;37(2):114–22.
  3. Pham T et al. Pain management in patients with chronic kidney disease. Nephrol Dialysis Transplant Plus 2009;2:111–18.
  4. Salisbury EM et al. Changing practice to improve pain control for renal patients. Postgrad Med J 2009;85(999):30–3.
  5. Gatchel RJ et al. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull 2007;133(4):581–624.
  6. Merskey H, Bogduk N (eds). Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms 2nd edn. Seattle: IASP Press;1994:210.
  7. Treede RD et al. Redefinition of neuropathic pain and a grading system for clinical use: consensus statement on clinical and research diagnostic criteria. Neurology 2008;70:1630–5. 
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  9. Dworkin RH et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85(3 Suppl):S3–14. 
  10. Chater S et al. Withdrawal from dialysis: A palliative care perspective. Clin Nephrol 2006;66(5):364–72.
  11. Davison SN. Pain in hemodialysis patients: prevalence, cause, severity, and management. Am J Kidney Dis 2003;42(6):1239–47.
  12. Turk DC, Melzack R (eds). Handbook of Pain Assessment. Guilford Press, New York;2011.
  13. Bennett M. The LANSS Pain Scale: The Leeds assessment of neuropathic symptoms and signs. Pain 2001;92(1-2):147–57.
  14. Haanpaa MN et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011;152(1):14–27.
  15. Barakzoy AS, Moss AH. Efficacy of the World Health Organization analgesic ladder to treat pain in end-stage renal disease. J Am Soc Nephrol 2006;17:3198–203.
  16. Oscier C et al. Paracetamol – a review of three routes of administration;2007. http://update.anaesthesiologists.org/wp-content/uploads/2008/12/Paraceta...
  17. McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain 5th edn. Elsevier, Churchill Livingstone China;2006:444.
  18. UK Medicines Information. Which opioids can be used in renal impairment? www.nelm.nhs.uk/en/Original-search/?parent=53949&query=which+opioids+can... (accessed 11 February 2013).
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