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could morphine-induced IL-2 suppression be causing low CD4?
Apr 23, 2008

Hi! I hope that this is the right forum to submit this question. Ive been on opiates for nearly 7 years. I started on Duragesic plus fentanyl lollipops prn until the fentanyl started hitting me funny, causing a lot more exhaustion, cloudy-headedness, and general stupidity than ever before. Then a week or so on Oxycontin, which I will NEVER take again because it made me feel just awful, unlike any other opiate Ive ever been prescribed. So, for the last 4 years or so, Ive been on sustained-release morphine (a cheaper version of MS Contin). Dose has been 90mg bid for a couple years. My VL has been suppressed below the level of detection for nearly a decade, with only a few transient exceptions and one treatment failure about six years ago. However, my CD4+ T-cell count has never really come back to where I would like it. I started at 15, and, excluding my first two years on treatment, it has nearly always been within the range of 210-340, but the average in the last five years has probably been somewhere around 280/15%. My CD8 count has dropped substantially, but the absolute number remains, on average, at over two times the upper limit of the reference range. Consequently, the CD4:8 ratio and CD8% are obviously skewed. For a while, I was trying various super-regimens a third nuke, an extra PI, even Fuzeon! - on the theory that the HIV might be replicating somewhere, even if there was no evident viremia. In retrospect this seems pretty silly, and I am currently very happy on Prezista, Norvir, and Truvada. However, recently I came across several articles online about the immunosuppressive effects of morphine everything from inhibition of type-I interferons and induction of lymphocyte apoptosis (e.g. http://cvi.asm.org/cgi/reprint/4/2/127.pdf) to inhibition of interleukin-2 (e.g recent abstract http://cat.inist.fr/?aModele=afficheN&cpsidt=18594404), and other articles mentioning possible negative effects on NK cells, CTLs, etc. I was particularly concerned about the direct and indirect effects on T-lymphocytes, and brought this up to my doctor, along with the possibility of switching to another opiate that might be less immunosuppressive (one study found that hydromorphone and oxycodone did not produce the same IL-2 inhibition http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1564723&blobtype=pdf) or trying to taper off of opiates altogether. My doctor was unaware of this research, but did not think that discontinuing the morphine would have any effect on my CD4 count. He also mentioned that hydromorphone was very addictive, even more so than morphine. My questions are the following: 1. Do you think the morphine is a contributing factor to the failure of my CD4 count to rebound more dramatically? 2. Given that Ive been on opiates for many years and have never abused them or taken them otherwise than prescribed, what is the likelihood that switching from morphine to hydromorphone could turn me into a drug addict? Even though Ive never abused opiates, I have abused IM Toradol (i.e. taken it for longer than the three days allowed, gotten prescriptions for it from more than one doctor...). 3. If the risk with hydromorphone is too high, could you recommend another painkiller that is less immunosuppressive than morphine, but no more addictive? I would prefer not to take oxycodone. 4. If the morphine is immunologically problematic, should I be concerned by the fact that my HIV doc, whom I otherwise trust and adore, either did not know this or never said anything, and does not think its a problem? Thank you so much!

Response from Dr. Young

Thanks for your post.

I understand your want for higher CD4s and your current counts and percentages support your interest. Nevertheless, I wouldn't be so hard on your doctor- this is a pretty obscure and poorly known observation.

That you started with such a low CD4 puts you at risk for slower rate and lower extent of CD4 recovery. It's not clear to me how the morphine observation ultimately affects your medical management. It would seem to me that you have a very serious, chronic pain scenario; without narcotics, I'd guess that your quality of life would be very negatively impacted. It is always reasonable to ask if there are alternatives to narcotics and perhaps a non-narcotic strategy could improve CD4s on the basis of this study.

As for a switch from morphine to hydromorphone, I would be surprised if this had any significant affect, since both act a the same molecular level, at the same opiate receptor.

So, we'd be looking at alternatives to opiate narcotics- frankly this requires a more detailed discussion about the type of pain your having and the underlying basis of the pain. Some patients benefit from adjunctive strategies, like Neurontin or Lyrica, other physical or surgical options may exist too.

I hope this is a helpful discussion.

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