Sickle Cell Disease (SCD) is a genetic haematological disorder that can cause acute painful crises of the condition. A mutation in the DNA causes the substitution of a single amino acid in the protein haemoglobin (haemoglobin-S) (Yusuf et al, 2011). Immature red blood cells called stress reticulocytes are released prematurely from the bone marrow (Hebbel, 1997). These stress reticulocytes express surface proteins that promote adhesion, typically used to retain the cell in the marrow. Hebbel (1997) and Bunn (1997) identified that the process of occlusion is two-fold: the stress reticulocytes become adhered to the vessel endothelium slowing blood flow which in turn causes the malformed, sickle-shaped erythrocytes to become clumped, trapped in the microcirculation occluding blood flow through the capillary network. The process of occlusion causes ischaemia and infarction of the distal tissues (Chiang Frenette, 2005). A vaso-occlusive crisis commonly presents as uncontrolled pain to the upper back, arm, chest and pelvis and can occur at any time as well as be provoked by stress, dehydration, altitude change and infection (McClish et al, 2009; Ahmed, 2011). Gladwin (2016) explains that SCD patients can suffer from severe complications due to the occlusion of micro-vessels. These complications include chronic kidney injury, acute chest syndrome as a result of infarction of the lung parenchyma, priapism, splenic sequestration, and cerebrovascular infarctions that contribute to the premature mortality that the disease causes (Platt et al, 1991; Manwani Frenette, 2013; Gladwin, 2016). This paper will examine the current analgesic pharmacotherapies available to paramedics attending patients with pain associated with a vaso-occlusive crisis (VOC). Current evidence will be reviewed and contrasted to make recommendations for further pharmacological agents for the management of intractable pain.
Current position
In 2004, the London Ambulance Service conducted a clinical audit of SCD patients. The review showed that subjective pain scoring was recorded poorly by crews and that eligible patients did not receive appropriate intravenous analgesia from a paramedic (London Ambulance Service NHS Trust, 2004). A follow-up clinical audit in 2011 indicated that the management of patients presenting with a vaso-occlusive crisis had improved regarding analgesia (London Ambulance Service NHS Trust, 2011). Both audits concluded that sickle cell patients were still not receiving adequate analgesia for their subjective pain scores. It is likely that the conclusions of these audits are broadly similar to other pre-hospital care services with experience of sickle cell patients since, with national clinical guidelines, paramedic practice in terms of analgesia does not tend to differ between services (Joint Royal Colleges Ambulance Liaison Committee and Association of Ambulance Chief Executives, 2016). The lack of adequate analgesia may be accounted for by clinicians assuming patients were displaying drug-seeking and opiate addiction behaviour (London Ambulance Service NHS Trust, 2011). In fact, some evidence has indicated that SCD patients have increased clearance and metabolism of morphine, and thus require higher doses to achieve an analgesic effect (Darbari et al, 2011). A minority of patients are repeat attendees at the Emergency Department which may lead to an impression of lack of control of their condition and drug-seeking behaviour (Aisiku et al, 2009). However, repeat attendees are those individuals who are experiencing more severe pain, and with a worse quality of life than non-repeat attendees due to the severity of their SCD (Aisiku et al, 2009).
The UK Ambulance Service Clinical Practice Guidelines currently recommend administration of Entonox unless for a prolonged period, followed by oral or subcutaneous morphine sulphate (Joint Royal Colleges Ambulance Liaison Committee and Association of Ambulance Chief Executives, 2016)
Entonox
Entonox has been a cornerstone of pain reduction analgesics for many years (Baskett Withnell, 1970). The use of Entonox for patients who are having a VOC is becoming contentious (Newcombe, 2002). Regular and extensive use of Entonox may cause irreversible neuropathy (Ougundipe et al, 1999). Ougundipe et al. (1999) reports the case of three patients who received prolonged Entonox treatment for SCD and developed paraesthesia as well as a peripheral sensorimotor neuropathy confirmed by nerve conduction studies. Ougundipe et al. (1999) postulated that since the serum B12 levels reduced in all three patients, the combination of a reduced serum B12 level and the nitrous oxide produced the neuropathy. Indeed, some hospital guidelines now recommend that Entonox is discontinued once a patient is handed over to the Emergency Department due to the risk of neuropathy (St Georges Healthcare NHS Trust, 2012). One case study has also illustrated the development of bone marrow suppression in the frequent and prolonged use of Entonox, but there was no relationship to the serum B12 level (Mather Sen, 2014)
Opiates
NICE (2012) recommend that the initial analgesic pharmacotherapy used in managing the pain resulting from a sickle cell crisis should be a potent opioid via any appropriate route. The literature indicates that all opiates should be administered intravenously (IV) (Glassberg, 2011). The subcutaneous route should only be used where intravenous access is not possible since its rate of absorption is unpredictable (McCullough, 2006).
Morphine and fentanyl are acceptable opiates for use in sickle cell crisis, with most literature recommending IV boluses or infusions until the patient's pain is reduced significantly, with the patient subsequently converting to an opiate Patient Controlled Analgesia (PCA) pump (Gonzalez et al, 1991). Intranasal delivery should also be considered especially in paediatric presentations where diamorphine intranasally has been shown to be effective (Telfer et al, 2009).
Robieux et al. (1992) conducted a trial of 66 patients split into two arms, comparing intermittent opioid administration with continuous IV infusion in children suffering from pain from SCD crisis. While the study concluded that continuous IV opioid infusion reduced the duration of pain significantly, this is currently not feasible in wider pre-hospital care since Houston and Pearson (2010) noted no ambulance services currently supply syringe pumps for use by all paramedics, however in recent years Specialist Paramedics in Critical Care have started to utilise syringe pumps. Van Beers et al. (2007) clarified in a randomised controlled trial that Patient Controlled Analgesia (PCA) is superior to continuous infusion since they result in higher morphine consumption to deliver the same reduction in pain scores. The superiority of PCA over intermittent IV boluses has been supported by Emergency Department studies, producing reasonable generalisability to the pre-hospital environment (Gonzalez et al, 1991).
National Clinical Guidelines currently recommend all morphine is administered subcutaneously in the pre-hospital environment (Joint Royal Colleges Ambulance Liaison Committee and Association of Ambulance Chief Executives, 2016). The use of implantable venous access devices and long-term central venous access are linked to higher incidences of thrombosis and bloodstream infection (Abdul-Rauf et al, 1995; Wagner et al, 2004; Shah et al, 2012). However, there was no literature examining the risk arising from standard Venflon catheters. It appears prudent to recommend that unless IV cannulation is aseptic, then morphine is administered subcutaneously. SCD is a risk factor for difficult venous access (thought to be from a history of repeated attempts and a build-up of scar tissue), and failed attempts can make access significantly more challenging to achieve when entering the in-hospital phase of patient management (Fields et al, 2014).
Adjuvants
A Cochrane Review in 2006 noted that the administration of parenteral non-steroidal anti-inflammatory drugs (NSAIDs) might reduce the dose of opioids needed to control pain (Dunlop Bennett, 2006). Lack of update resulted in the review's withdrawal in 2013. NICE (2012) recommend that all acute sickle cell crisis patients receive regular paracetamol and NSAIDs to address their pain unless contraindicated.
Ketorolac is a potent IV NSAID (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2016). Studies undertaken with paediatric sickle cell patients indicated that continuous infusion of ketorolac might have an opiate sparing effect, whereas single boluses may not (Hardwick et al, 1999; Perlin et al, 1994). A study of 25 patients randomised to ketorolac or placebo groups illustrated that ketorolac reduces subjective pain and morphine requirements postoperatively in spinal patients (Cassinelli et al, 2008). Although it may produce slight opiate sparing effects, ketorolac can also have significant renal complications in patients who have a reasonable likelihood of impaired renal function and should be used judiciously (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2016).
Ketamine
Low-dose (sub-dissociative) ketamine represents a new development in the treatment of acute sickle cell crisis pain (Uprety et al, 2014). Ketamine has been used safely for pain management in the Emergency Department (Lester et al, 2010), and Ambulance Services are starting to realise its potential as a potent but relatively safe analgesic for the out-of-hospital environment (McQueen et al, 2014).
Tawfic, Farris and Kausalya (2014) performed a retrospective analysis of nine acute sickle cell crisis patients who were given bolus doses of ketamine and midazolam and then started on ketamine and midazolam infusions. Tawfic, Farris and Kausalya (2014) noted that there was a significant improvement in pain scores, and the average morphine requirement per day was reduced, perhaps indicating a synergistic relationship between ketamine and opioid analgesia. Small-scale paediatric trials, case reports and literature reviews also support the use of ketamine infusions (Zempsky et al, 2010; Gowhari et al, 2013; Uprety et al, 2014). It is important to note that all these studies rely on infusions of ketamine, something which may be prohibitively complex to carry out in the out-of-hospital environment. Studies comparing bolus dosing and infusion are required to ascertain whether infusion is superior to bolus dosing since bolus dosing is simpler to replicate in the pre-hospital environment.
Conclusion and recommendations
SCD and its presentation to the ambulance service in the form of vaso-occlusive crisis is a serious condition with severe complications resulting in a premature mortality (Manwani Frenette, 2013; Gladwin, 2016). Pain in this patient group is thought to be significantly under-treated, perhaps due to an incorrect assumption of addictive behaviour; however, evidence indicates that SCD patients require higher doses of morphine than other patients (London Ambulance Service NHS Trust, 2011; Darbari et al, 2011; Aisiku et al, 2009). Entonox should no longer be given routinely to manage pain in sickle cell crisis patients unless other pharmacological or non-pharmacological means have failed to address their pain sufficiently due to the risk of neuropathy (Ougundipe et al, 1999; Mather Sen, 2014). Opiates, for example, morphine, should be provided promptly and in IV boluses unless IV access is not possible, delayed, unobtainable or could not be performed aseptically. Oral, subcutaneous or intranasal doses are then acceptable (McCullough, 2006; Van Beers et al, 2007; Shah et al, 2012). Services should investigate the use of intranasal diamorphine for SCD patients in intractable pain (Telfer et al, 2009). Paracetamol and NSAIDs should also be administered concomitantly (National Institute of Clinical Excellence, 2012). Future treatment for sickle cell crisis pain may include ketamine, midazolam and IV NSAIDs, but any changes in analgesia should take place in conjunction and with the oversight of haematological centres (Okpala et al, 2002).