Professor Kalpna Gupta, who works at the University of Minnesota in the US, gave an interesting talk at the 9th Sickle Cell & Thalassaemia Conference in London last week. The talk covered her investigations into the use of cannabis as an option to manage sickle cell pain, and her ground breaking work looking at the mechanisms of chronic pain in patients with sickle cell disease.
Cannabis can be used successfully to manage pain in multiple sclerosis, HIV/AIDS and cancer and is authorised for medical use in those conditions; so why not sickle cell? In fact, many individuals with sickle cell already use cannabis. A study in London in 2005, based at the Central Middlesex Hospital, found that 36% of patients had used cannabis over the previous 12 months, mainly by smoking. Most, 52%, had used the drug to relieve pain, but 39% used it primarily to induce relaxation and to reduce stress, anxiety and depression.
Professor Gupta used a strain of transgenic mice, or mice which have been genetically altered so they have sickle cell disease, to investigate the effects of cannabis on pain behaviour.
The team found specific neurochemical changes in the peripheral tissues and in the spinal cord, which were thought explain the increased sensitivity to pain exhibited by the sickle cell mice. They also demonstrated that chemical compounds, similar to cannabis, increased the pain threshold of the mice to much the same extent as morphine. As a result of these positive findings Professor Gupta has teamed up with Dr Abrams, from San Francisco General Hospital to investigate the use of vapourised cannabis in the management of chronic sickle cell pain in patients. The trial started recruiting subjects in August 2014 and is due to report next year, details here:
But something else, which may be very important, also came out of these studies on sickle cell mice. The new findings link together two phenomena which we all recognise. Firstly, any one who has been given morphine, or other opiates, for pain relief will know that one of the most unpleasant side effects is the terrible itching that sometimes occurs. Secondly, as the PiSCES study in 2005 demonstrated, about one third of sickle cell patients have chronic, daily pain, as well as intermittent painful crises. Chronic pain is difficult to understand and often dismissed or poorly treated. These patients are said to have hyperalgesia, or an increased sensitivity to pain, and often experience relatively mild sensations as unpleasant pain. How are these two phenomena be connected?
See previous blogs “Chronic Pain Conference” 14/12/2014 and 17/12/2014 for a more detailed description of chronic pain.
Professor Gupta discovered that there are key cells, called mast cells, in the skin and spinal cord of sickle cell mice, which are both increased in number and partially activated. When they are activated the mast cells secrete a variety of chemicals, which latch onto nearby nerve endings making the nerves more sensitive to painful stimuli. In other words the substances released by mast cells induce a state of hyperalgesia. This is the first time anyone has demonstrated a convincing biochemical mechanism to explain hyperalgesia and chronic pain. Not only that, but another one of the chemicals released by the mast cells is histamine, and it is this which is responsible for the intolerable itching associated with morphine.
The biochemistry is complicated, so skip this paragraph if you don’t want to know!
The mast cells are thought to be in a state of constant activation due to the effects of both inflammatory mediators, such as interleukins, and bone marrow stimulating factors, such as GM-CSF, both of which are present in increased concentrations in sickle cell blood. Activated mast cells release a variety of chemicals, including tryptase and substance P which, via the PAR-2 receptor, stimulate local pain nerve fibres (unmyelinated C fibres) to release neuropeptides. These neuropeptides, substance P and calcitonin gene related peptide (CGRP), promote tissue inflammation, so called neurogenic inflammation, by stimulating vaso-dilatation and plasma extravasation, they also importantly heighten the sensitivity of pain nerve fibres to nociceptive, or painful, stimuli.
This is all very well but what is so exciting is that it is easy to stabilise mast cells using drugs which are already in common use in other areas of medicine. Two drugs are available, imatinab, used to treat some forms of chronic leukaemia, and cromolyn sodium, used to treat asthma. When Professor Gupta’s team did the experiments the results were unequivocal. By stabilising mast cells both drugs broke the vicious cycle, increased the pain threshold in the mice and abolished the state of hyperalgesia.
Now, if it was possible to do this in patients with sickle cell disease the effects maybe dramatic. Well, in fact, it turns out that the experiment has already been done. In 2011 a team of doctors from Paris, in France, reported an unfortunate man with sickle cell anaemia who developed chronic myeloid leukaemia (CML) at the age of 25 years. Standard treatment for this form of leukaemia is the drug imatinab. One year later there was no evidence of leukaemia and he had not had a single episode of pain. He noticed that if he forgot to take the imatinab then sickle pain started to return within 2-3 days but disappeared again once he started back on the drug. A very similar case from Florida was briefly reported in 2009 and more fully last year. It is now clear that in these two patients imatinab is benefiting the sickle cell by both stabilising and reducing the number of mast cells.
Professor Gupta concluded her talk by saying that mast cells are a newly discovered aspect of sickle cell and that they are potentially modifiable by drug therapy. Lets hope there is further work in the near future looking at the feasibility of using imatinab or related drugs in sickle cell patients, particularly those with chronic pain.
Mast cell activation contributes to sickle cell pathobiology and pain in mice. Lucile Vincent, Derek Vang, Julia Nguyen, Mihir Gupta, Kathryn Luk, Marna E. Ericson, Donald A. Simone, and Kalpna Gupta. Blood 2015, volume 122, pages 1853-1862
Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids. Divyanshoo R. Kohli, Yunfang Li, Sergey G. Khasabov, Pankaj Gupta, Lois J. Kehl, Marna E. Ericson, Julia Nguyen, Vinita Gupta, Robert P. Hebbel, Donald A. Simone, and Kalpna Gupta. Blood 2010, volume 116, pages 456-465
Understanding pain and improving management of sickle cell disease: the PiSCES study. Wally R. Smith, Viktor E. Bovbjerg, Lynne T. Penberthy, Donna K. McClish, James L. Levenson, John D. Roberts, Karen Gil, Susan D. Roseff, and Imoigele P. Aisiku. Journal of the National Medical Association 2005, volume 97, pages 183-193
Cannabis use in sickle cell disease: a questionnaire study. Howard J, Anie KA, Holdcroft A, Korn S, Davies SC. British Journal of Haematology 2005, volume 131, pages 123-128