Clinicians should have in mind, during the assessment of pain and planning of pain management approaches, the pharmacokinetics and pharmacodynamics of an analgesic agent administered in the presence of Chronic Kidney Disease with reduced or no Glomelural Filtration Rate (Table 2). Both are complex in patients with Chronic Kidney Disease (Davison 2003, Dean 2004, Cohen et al. 2006, Douglas et al. 2009, Tawfic &
Bellingham 2015, Wu et al. 2015). Furthermore, consideration should be given to the effects of analgesic agents in a continuously aging renal population.
6.3.1 Analgesics
By the end of 1980, the World Health Organisation (WHO) identified the absence of national policies on pain relief (Brooksbank 2009) and published the Analgesic Ladder to Treat Pain (WHO 1986) which was revised in 1997. The WHO Analgesic Pain Ladder is the pathway for healthcare professionals in their journey to manage pain. At the beginning the WHO analgesic ladder was addressing only cancer pain, attributing in the realisation of the importance of pain management (WHO 1996, Launay-Vacher et al. 2005, Golan et al. 2009).
It proposed gradual use of analgesics, starting in step one with non-opioid (Aspirin, Acetaminophen, Non-Steroid Anti-Inflammatory drugs) for mild to moderate pain, going to step two to weak opioids (Codeine, Oxycodone) for mild and average pain and continuing to step three with stronger opioids (Morphine, Hydromorphone, Methadone) for average and severe pain combined with other medications, such as tricyclic antidepressants, spasmolytic, antihistaminic, benzodiazepine, corticosteroids. Finally, in step four it is proposed to have nerve block, epidural anaesthesia or patient controlled analgesia (Kurella et al. 2003). The effectiveness of the WHO analgesic ladder has been reported to be 70-80%
(Jadad et al. 1995, Heiwe & Bjuke 2009, Steinberg et al. 2011, Lema 2012).
In the case of renal patients the WHO Analgesic Ladder has been proven to be equally effective (Barakzoy & Moss 2006). Medication selection process should take into account the type and duration of pain, as well as the Renal Replacement Therapy mode (Haemodialysis or Peritoneal Dialysis) that the individual is on. If the chosen pharmacological agent is mostly cleared by non-renal mechanisms, such as the liver, its clearance is not affected by dialysis. The removal of the agent through dialysis depends on its molecular weight, protein binding, volume of distribution, and solubility. More molecules are passing through the dialyser (filter) when the molecular weight is low, whereas the greater the protein binding, the less the molecule is removed. In a similar way, less molecules are removed when the water solubility is high, whereas the greater the volume of distribution, the less molecule is removed per time unit (Dean 2004, Hardy & Reymond 2007). In haemodialysis the removal of molecules is influenced by the dialysate and blood flow rates, the dialysers’ (filter) surface area and capillaries size. The higher the flow rates and the efficiency of the dialyser (high-flux dialyser), the higher is the removal of a medication molecule. In case of peritoneal dialysis, as it has already been mentioned in the second chapter, the dialyser is the patient’s peritoneum, which unfortunately cannot be altered as in haemodialysis. The removal of an agent depends on the permeability of the peritoneum, the volume and consistency of the dialysate and the frequency of the exchanges per day. The more exchanges, the more medication molecules are removed (Dean 2004).
6.3.2 Non-steroidal Anti-inflammatories (NSAIDs)
Non-Steroidal Anti-inflammatories (NSAIDs) are used as first-line agents to control pain in the general population and in renal colics (Holgate & Pollock 2004, Hȍrl 2010), but administration to renal patients should be with caution and should be limited to few days
per time due to renal toxicity, and gastric ulceration. Gastrointestinal bleeding should be a concern due to the fact that most Chronic Kidney Disease stage 5 patients have uraemic platelet dysfunction and are prone to bleeding (Cohen & Davison 2015). Furthermore, if administered, close monitoring of renal function is necessary, as it has been proven to have negative effect on residual kidney function. NSAIDs are not allowed for long-term use and should be avoided (Bajwa et al. 2001, Kurella et al. 2003, Cohen et al. 2006, Plantinga et al.
2011, Pan et al. 2014). All NSAIDs have a ceiling on analgesic benefits and are often insufficient for severe pain (Davison 2003, Hȍrl 2010).
Acetaminophen (for USA and Japan) or Paracetamol is recommended by the National Kidney Foundation (NKF 2014) as the first analgesic of choice for Chronic Kidney Disease patients. It is a simple and safer alternative to NSAIDs, as it lacks risk of gastric ulceration and platelet dysfunction. Therapeutic dosage can be started at a 500-650mg orally every six hours, and if pain is not relieved a 1000mg every four to six hours dose can be administered.
No more than 4000mg per day are allowed due to hepatotoxicity (Bajwa et al. 2001, Kurella et al. 2003, Cohen et al. 2006, Evans et al. 2009, Hogan & Norby 2010, Kuo et al. 2010). Its use should be discouraged on a constant base (Bailie et al. 2004). If liver disease is present, along with Chronic Kidney Disease, Acetaminophen administration is prohibited (Bolesta & Haber 2002, Mazer & Perrone 2008).
COX-2 selective inhibitors, such as Rofecoxib, Etoricoxib and Celecoxib, have been launched in the 1990s as substitutes of acetaminophen and NSAIDs with the same analgesic action but without any platelet adverse effects. It is found that COX-2 agents have also potential negative effect on renal function and must be used with caution in patients with mild to moderate renal insufficiency and avoided in severe renal impairment (Swan et al.
2000, Hörl 2010). They can cause qualitative changes in GFR, sodium retention, and development of peripheral oedema (Brater et al. 2001), may affect blood pressure less than NSAIDs and increase the risk for Acute Renal Failure (ARF) especially in the elderly treated with ACE inhibitors or angiotensin II blockers, diuretics and NSAIDs (Bajwa et al. 2001, Hörl 2010).
6.3.3 Opioid agents
Opioid agents are used either as monotherapy for pain or in conjunction with other analgesics. They are not without adverse effects. The most common are alterations in mental status, respiratory depression, nausea or constipation (which is catastrophic for PD patients).
In Chronic Kidney Disease patients opioids can accumulate due to impaired renal function.
In case of opioids administration, caution should be given due to the fact that uremic symptoms may mimic adverse effects of opioids, resulting in withdrawal of the analgesics (Davison 2003, Mercadante & Arcuri 2004, Bulter et al. 2014).
6.3.3.1 Opiates
Morphine is a low protein-binding molecule and the most commonly used opioid.
Morphine-6-glucuronide (M6G), an active metabolite of Morphine, is excreted by the kidneys and accumulates in patients with Chronic Kidney Disease stage 5 giving opiate toxicity with adverse effects, such opioid neurotoxicity, sedation, respiratory depression and prolonged duration (Angst et al. 2000, Davison 2005). It has moderate water-solubility, so it is removed by most dialysis procedures (Dean 2004, Hardy & Reymond 2007). The rate of morphine removal in haemodialysis patients depends on the ultrafiltration and dialysate flow rates (Jamal et al. 1998, Mercadante & Arcuri 2004), whereas in peritoneal dialysis systemic morphine clearance might be in the normal range but M6G metabolite has been shown to accumulate (Mercadante & Arcuri 2004, Butler et al. 2014).
Codeine can be either naturally extracted from Morphine or be technically produced. The semi-synthetic agent is used for pharmaceutical reasons. Its analgesic effects are produced,
6.3 MEDICATION THERAPY
Clinicians should have in mind, during the assessment of pain and planning of pain management approaches, the pharmacokinetics and pharmacodynamics of an analgesic agent administered in the presence of Chronic Kidney Disease with reduced or no Glomelural Filtration Rate (Table 2). Both are complex in patients with Chronic Kidney Disease (Davison 2003, Dean 2004, Cohen et al. 2006, Douglas et al. 2009, Tawfic &
Bellingham 2015, Wu et al. 2015). Furthermore, consideration should be given to the effects of analgesic agents in a continuously aging renal population.
6.3.1 Analgesics
By the end of 1980, the World Health Organisation (WHO) identified the absence of national policies on pain relief (Brooksbank 2009) and published the Analgesic Ladder to Treat Pain (WHO 1986) which was revised in 1997. The WHO Analgesic Pain Ladder is the pathway for healthcare professionals in their journey to manage pain. At the beginning the WHO analgesic ladder was addressing only cancer pain, attributing in the realisation of the importance of pain management (WHO 1996, Launay-Vacher et al. 2005, Golan et al. 2009).
It proposed gradual use of analgesics, starting in step one with non-opioid (Aspirin, Acetaminophen, Non-Steroid Anti-Inflammatory drugs) for mild to moderate pain, going to step two to weak opioids (Codeine, Oxycodone) for mild and average pain and continuing to step three with stronger opioids (Morphine, Hydromorphone, Methadone) for average and severe pain combined with other medications, such as tricyclic antidepressants, spasmolytic, antihistaminic, benzodiazepine, corticosteroids. Finally, in step four it is proposed to have nerve block, epidural anaesthesia or patient controlled analgesia (Kurella et al. 2003). The effectiveness of the WHO analgesic ladder has been reported to be 70-80%
(Jadad et al. 1995, Heiwe & Bjuke 2009, Steinberg et al. 2011, Lema 2012).
In the case of renal patients the WHO Analgesic Ladder has been proven to be equally effective (Barakzoy & Moss 2006). Medication selection process should take into account the type and duration of pain, as well as the Renal Replacement Therapy mode (Haemodialysis or Peritoneal Dialysis) that the individual is on. If the chosen pharmacological agent is mostly cleared by non-renal mechanisms, such as the liver, its clearance is not affected by dialysis. The removal of the agent through dialysis depends on its molecular weight, protein binding, volume of distribution, and solubility. More molecules are passing through the dialyser (filter) when the molecular weight is low, whereas the greater the protein binding, the less the molecule is removed. In a similar way, less molecules are removed when the water solubility is high, whereas the greater the volume of distribution, the less molecule is removed per time unit (Dean 2004, Hardy & Reymond 2007). In haemodialysis the removal of molecules is influenced by the dialysate and blood flow rates, the dialysers’ (filter) surface area and capillaries size. The higher the flow rates and the efficiency of the dialyser (high-flux dialyser), the higher is the removal of a medication molecule. In case of peritoneal dialysis, as it has already been mentioned in the second chapter, the dialyser is the patient’s peritoneum, which unfortunately cannot be altered as in haemodialysis. The removal of an agent depends on the permeability of the peritoneum, the volume and consistency of the dialysate and the frequency of the exchanges per day. The more exchanges, the more medication molecules are removed (Dean 2004).
6.3.2 Non-steroidal Anti-inflammatories (NSAIDs)
Non-Steroidal Anti-inflammatories (NSAIDs) are used as first-line agents to control pain in the general population and in renal colics (Holgate & Pollock 2004, Hȍrl 2010), but administration to renal patients should be with caution and should be limited to few days
per time due to renal toxicity, and gastric ulceration. Gastrointestinal bleeding should be a concern due to the fact that most Chronic Kidney Disease stage 5 patients have uraemic platelet dysfunction and are prone to bleeding (Cohen & Davison 2015). Furthermore, if administered, close monitoring of renal function is necessary, as it has been proven to have negative effect on residual kidney function. NSAIDs are not allowed for long-term use and should be avoided (Bajwa et al. 2001, Kurella et al. 2003, Cohen et al. 2006, Plantinga et al.
2011, Pan et al. 2014). All NSAIDs have a ceiling on analgesic benefits and are often insufficient for severe pain (Davison 2003, Hȍrl 2010).
Acetaminophen (for USA and Japan) or Paracetamol is recommended by the National Kidney Foundation (NKF 2014) as the first analgesic of choice for Chronic Kidney Disease patients. It is a simple and safer alternative to NSAIDs, as it lacks risk of gastric ulceration and platelet dysfunction. Therapeutic dosage can be started at a 500-650mg orally every six hours, and if pain is not relieved a 1000mg every four to six hours dose can be administered.
No more than 4000mg per day are allowed due to hepatotoxicity (Bajwa et al. 2001, Kurella et al. 2003, Cohen et al. 2006, Evans et al. 2009, Hogan & Norby 2010, Kuo et al. 2010). Its use should be discouraged on a constant base (Bailie et al. 2004). If liver disease is present, along with Chronic Kidney Disease, Acetaminophen administration is prohibited (Bolesta & Haber 2002, Mazer & Perrone 2008).
COX-2 selective inhibitors, such as Rofecoxib, Etoricoxib and Celecoxib, have been launched in the 1990s as substitutes of acetaminophen and NSAIDs with the same analgesic action but without any platelet adverse effects. It is found that COX-2 agents have also potential negative effect on renal function and must be used with caution in patients with mild to moderate renal insufficiency and avoided in severe renal impairment (Swan et al.
2000, Hörl 2010). They can cause qualitative changes in GFR, sodium retention, and development of peripheral oedema (Brater et al. 2001), may affect blood pressure less than NSAIDs and increase the risk for Acute Renal Failure (ARF) especially in the elderly treated with ACE inhibitors or angiotensin II blockers, diuretics and NSAIDs (Bajwa et al. 2001, Hörl 2010).
6.3.3 Opioid agents
Opioid agents are used either as monotherapy for pain or in conjunction with other analgesics. They are not without adverse effects. The most common are alterations in mental status, respiratory depression, nausea or constipation (which is catastrophic for PD patients).
In Chronic Kidney Disease patients opioids can accumulate due to impaired renal function.
In case of opioids administration, caution should be given due to the fact that uremic symptoms may mimic adverse effects of opioids, resulting in withdrawal of the analgesics (Davison 2003, Mercadante & Arcuri 2004, Bulter et al. 2014).
6.3.3.1 Opiates
Morphine is a low protein-binding molecule and the most commonly used opioid.
Morphine-6-glucuronide (M6G), an active metabolite of Morphine, is excreted by the kidneys and accumulates in patients with Chronic Kidney Disease stage 5 giving opiate toxicity with adverse effects, such opioid neurotoxicity, sedation, respiratory depression and prolonged duration (Angst et al. 2000, Davison 2005). It has moderate water-solubility, so it is removed by most dialysis procedures (Dean 2004, Hardy & Reymond 2007). The rate of morphine removal in haemodialysis patients depends on the ultrafiltration and dialysate flow rates (Jamal et al. 1998, Mercadante & Arcuri 2004), whereas in peritoneal dialysis systemic morphine clearance might be in the normal range but M6G metabolite has been shown to accumulate (Mercadante & Arcuri 2004, Butler et al. 2014).
Codeine can be either naturally extracted from Morphine or be technically produced. The semi-synthetic agent is used for pharmaceutical reasons. Its analgesic effects are produced,
partly, through the biotransformation to Morphine. When perscribed orally, it is not administered as monotherapy but, usually, in combination with a non-opioid agent, such as Paracetamol. It is renally excreted and it should be avoided in patients with renal problems or on haemodialysis due to serious adverse effects caused (Dean 2004, Butler et al. 2014).
6.3.3.2 Semi-synthetic opiates
Hydromorphone is another opioid agent, with high water solubility, low molecular weight, low volume of distribution (Dean 2004) and with shorter duration of action and renal excretion compared to Morphine (Davison 2005). In the early 1990s, ithas been reported that Hydromorphone was probably the causative factor for myoclonus as a major adverse effect (Fainsinger et al. 1993) although less than those caused by Morphine. In case of administration close monitoring for signs of toxicity is necessary (Quigley 2002, Cohen et al.
2006). In the early 2000s, it was proposed that haemodialysis reduces Hydromorphone’s plasma levels by 40% of the pre-dialysis levels (Durnin et al. 2001) and that it is safe and effective to use it in dialysis patients (Lee MA et al. 2001). Later on, it has been shown that Hydromorphone is not effectively removed by haemodialysis, but still it does not accumulate in haemodialysis patients, probably due to rapid conversion to its metabolite (Hydromorphone-3-glucoronide, H3G) (Davison 2007b). The controversial findings should make the healthcare professional very cautious as to the use of the specific agent.
Another semisynthetic opioid, Oxycodone, with greater volume distribution than Hydromorphone, 50% protein-bound and quite water-soluble, should be administered with caution in Chronic Kidney Disease patients (Cohen et al. 2006). Its physicochemical properties suggest that its clearance is affected by hepatic and renal dysfunction and its elimination is impaired in Chronic Kidney Disease patients (Mercadante & Arcuri 2004).
6.3.3.3 Synthetic opiates
Pain can be managed with Meperidine or Pethidine, a synthetic opioid agent, and its metabolite (Normeperidine) are excreted unchanged in the urine, and have almost double plasma half-life in the presence of renal failure (Hassan et al. 2000). In addition, the onset of seizures has been reported in patients with impaired Glomerular Filtration Rate on haemodialysis or peritoneal dialysis (Hall & Sykes 2004). The use of Meperidine should be strictly avoided in the presence of Chronic Kidney Disease. Furthermore, research has shown that to some extent it is dialysed (Dean 2004).
Methadone, another synthetic opioid, mainly used in the management of dependence, has been shown to prevent glutamate excito-toxicity and to decrease opioid tolerance, which has been implicated in the pathogenesis of chronic pain (Hewitt 2000). Methadone has high volume of distribution and protein binding, low molecular weight and moderate water solubility. It is primarily metabolised in the liver and is excreted mainly in the feces, although almost 20% of it is excreted unchanged in the urine. Research has shown that Methadone is not removed by dialysis. In patients with anouria its excretion in the feces is enhanced with limited accumulation in plasma (Kreek et al. 1980, Furlan et al. 1999, Hardy & Reymond 2007). It can be an effective analgesic in patients with Chronic Kidney Disease, as described above.
Fentanyl, a rapid-onset, synthetic opioid, is commonly used for analgesia during anaesthesia. It has less adverse effects than Morphine with better cardiovascular stability and can be used for pain management. Fentanyl, with low water solubility, high volume of distribution and protein binding, and a moderate molecular weight, is rapidly metabolised in the liver with 5-10% excreted unchanged in the urine. However, Fentanyl extraction can be inhibited by uraemia and administration in Chronic Kidney Disease stage 5 patients should be with extreme caution and close monitoring (Bower 1982, Koehntop & Rodman 1997). In the late 1990s it was thought that in haemodialysis patients Fentanyl was dialysed
(Joh et al. 1998). More recent research shows that the specific agent is not removed by most dialysers, so pain control is sufficient (Hardy & Reymond 2007).
Another centrally acting opioid which is used for moderate to severe pain is Tramadol. It is not without complications and caution must be given as it can cause nausea, somnolence, constipation, and vomiting (Bajwa et al. 2001) or respiratory depression (Barnung et al. 1997).
Furthermore, 90% of Tramadol and its metabolites are excreted by the kidneys, and dose adjustment is obligatory in Chronic Kidney Disease patients as its elimination half-life is increased almost twofold. The maximum recommended dose should not exceed 50-100mg twice a day (Kurella et al. 2003) and increased dosage intervals are required (Mercadante &
Arcuri 2004, Turner et al. 2007).
Finally, Propoxyphene, another synthetic opioid, is metabolised to Norpropoxyphene which can cause cardiotoxicity that cannot be reversed with naloxone, central nervous system as well as respiratory depression in renal patients on dialysis. In addition, propoxyphene metabolites accumulate in Chronic Kidney Disease stage 5 and should not be used (Baillie et al. 2004, Cohen et al. 2006). However, in the early stages of Chronic Kidney Disease and in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and cyst haemorrhage, it can be administered in scheduled doses until pain subsides (Hogan &
Norby 2010).
6.3.4 Adjuvant therapies
Adjuvant medications are considered those that are not primary designed for pain management. Antidepressants, tricyclic (TCAs) and Tetracyclic (TeCAs), and anticonvulsants have been proven to pe effective in neuropathic pain management, with the first being the first-line treatment for neuropathic pain in patients with normal renal function (Cohen & Davison 2015). Dose adjustment is mandatory in the case of Chronic Kidney Disease patients, due to anticholinergic and cardiac adverse effects.
6.3.4.1 Anticonvulsant agents
Anticonvulsant agents, such as Gabapentin and Pregabalin have been effectively used for neuropathic pain, in healthy population (Dworkin et al. 2007) and in Chronic Kidney Disease patients (Cohen & Davison 2015).
Gabapentin is mainly used for neuropathic pain but it accumulates in Chronic Kidney Disease, as it is excreted in the urine unchanged (Spaia et al. 2009, Zand et al. 2010). Research
Gabapentin is mainly used for neuropathic pain but it accumulates in Chronic Kidney Disease, as it is excreted in the urine unchanged (Spaia et al. 2009, Zand et al. 2010). Research