Pharmacological treatment for avascular necrosis pain in sickle cell disease and beta thalassemia
Cerati G ClaudioAbstract
Background
Avascular necrosis (AN) in sickle cell disease (SCD) represents one of the main causes of pain . Sickle cell disease represents a group of inherited hemoglobin disorders all of which include the presence of HbS with the result of abnormally shaped red blood cells that are prone to hemolysis and adhesion. The appearance of clinical signs of AN at early ages in patients with SCD were yet described (Ref N°1). Clinical evolution of this condition should be closely checked by different diagnostic means ( Rx, Magnetic resonance) through whole life in order to prevent serious side events since SCD represents a prevalent and progressive complication in young patients with long-term mobility impairment requiring for example hip arthroplasty at a median age of 35 years in patients early diagnosed at a median age of 9 years. In young children with SCD and AVN causing mobility issues, physiotherapy based on maintaining joint range of motion (ROM) focusing on pain relief , muscle strengthening and reduction of joint stress are a first election in clinical practice whilst severe cases require surgery being patient adherence on a long term a critical issue (Ref N°2). Pain treatment for AVN include anti-inflammatory drugs like Ibuprofen, Naproxen or Celecoxib.More stronger pain medications are often used like Oxycodone in the US or Tramadol, Codeine or Morphine in Costa Rica (Ref N°3)
Methods
In order to enhance analgesic potential and obviate side effects of opioid or non opioid analgesics many alternatives were tested such as using adjuvants like antihistamines, benzodiazepines, anticonvulsants and so on , however chronic use of them in oral pharmaceutical forms or injectable ones. As Ibuprofen was early used as anti inflammatory and analgesic , the author thought that an Ibuprofen like molecule (Flurbiprofen) could be of use based on the fact that this API acts as an inhibitor of inflammasome NLRP3 in mouse model of sickle cell disease .(Ref 5) It was early described how R Flurbiprofen acts in neuropathic pain inhibiting cyclooxygenase 2 (cox 2) blocking arachidonoylglycerol (2-AG)oxidation (Ref 4), Nerve regeneration by joint administration of Vitamins B1, B6 and B12 was also described by Oscar Cuyubamba et al.(Ref N°6). Nanoencapsulation of drugs usually used for dissolution enhancement also interacts with red blood cell membrane (RBC) and depending on several variables they can be attached to the membrane or otherwise be engulfed by RBCs Materials: Tadalafil API , Flurbiprofen API and Vitamins B1,B6 and B12 were encapsulated by Polymicrocaps polymer encapsulation technology .Thioctic acid was used both as penetration enhancer in the transdermal patch and encapsulation material . Poloxamer 188 was used as surfactant agent.
Results
Transdermal penetration of drugs from the patch was followed by measuring initial concentration of API’s in the patch (APIiCC) and APÍs concentration remaining at different times (APIfirst hour CC, APIthird hour CC, APIsix hour CC and APIfinal CC) (Table N°1). Dermal penetration was directly observed by the red coloring of Vitamin B12 nanoparticles (Figure N°1) on the skin. Clinical signs were followed by Hip magnetic resonance at the initial stage of the treatment (Figure 3) and the first year of it (Figure 4) comparing average number and diameter of subchondral geodes.
Conclusions
Being both Thalassemia and Sickle cell diseases genetic conditions , it is not expected to reach a cure of both them , instead of this , lowering pain condition to a point that allows the patient to carry on a normal life would be a must. Medical follow up of this treatment concluded that there was no negative advancement of the condition since an equilibrium between necrosis and osteogenesis was achieved. Dosage adjustment based on patient condition or standardization for a group of patients with similar clinical conditions should be carried on since this is a single case.