Drug trial cuts chronic pain’s opi­ates need

Aus­tralian re­search is paving the way for a new class of non-ad­dic­tive painkillers, writes Lyn­nette Hoff­man

The Weekend Australian - Travel - - Health -

IT wasn’t un­til af­ter surgery abated her need for huge doses of mor­phine that one South Aus­tralian wo­man re­alised how much the med­i­ca­tion she had been tak­ing for her back pain had been dis­rupt­ing her life. Her en­ergy re­turned. She was no longer con­stantly sleepy. Her con­cen­tra­tion im­proved and she could once again drive. It’s a sce­nario that is far from un­com­mon. But ex­am­ples like this il­lus­trate one of the most ex­as­per­at­ing as­pects of chronic pain — that the side ef­fects of the drugs used to treat it can some­times be nearly as de­bil­i­tat­ing as the pain it­self, says Mark Hutchin­son, a Univer­sity of Ade­laide post-doc­toral fel­low who is work­ing with other ex­perts in Amer­ica to change that.

Peo­ple of­ten build up tol­er­ance to the med­i­ca­tion, re­quir­ing big­ger and big­ger doses to achieve the same anal­gesic ef­fect, and in­creas­ing the like­li­hood of side ef­fects which, in ad­di­tion to those de­scribed above, can also in­clude con­sti­pa­tion and dry mouth.

On top of that, mor­phine and other opi­ates are highly ad­dic­tive, caus­ing crav­ings and cre­at­ing the risk that other fam­ily mem­bers or vis­i­tors to the house not au­tho­rised to re­ceive the drug may get hold of it.

But new re­search by a team of sci­en­tists from the Univer­sity of Ade­laide and the Univer­sity of Colorado is paving the way for a new class of non-ad­dic­tive drugs to treat neu­ro­pathic pain, in which the nerve fi­bres them­selves be­come dam­aged and send in­cor­rect sig­nals.

Most chronic pain is neu­ro­pathic. Af­ter the orig­i­nal in­jury, such as a bro­ken leg or a neck strain, has healed, the nerves some­times fail to re­turn to nor­mal and keep send­ing a pain sig­nal when there is no po­ten­tially harm­ful ex­ter­nal stim­uli to jus­tify it.

Univer­sity of Ade­laide pro­fes­sor of clin­i­cal phar­ma­col­ogy Paul Rolan has led clin­i­cal tri­als to look at the ef­fects of a drug called AV411 on pa­tients with neu­ro­pathic pain. AV411 has been used in Asia to treat asthma for decades, but the small-scale clin­i­cal tri­als at the univer­sity’s Pain and Anaes­the­sia Re­search Clinic were the first to test its use for pain re­lief.

Pa­tients were given AV411 along with what­ever painkillers they were al­ready tak­ing. They were told they could re­duce the dosage of other painkillers as they saw fit.

‘‘ We didn’t see a ma­jor dif­fer­ence in pain lev­els, but what we did see was a sig­nif­i­cant re­duc­tion in the doses of opi­oids that were re­quired. Peo­ple were need­ing less strong pain killers,’’ says Rolan, who pre­sented the early find­ings at an in­ter­na­tional con­fer­ence on neu­ro­pathic pain in Salt Lake City, Utah in Novem­ber.

If lower doses can be given, it has the po­ten­tial to re­duce side ef­fects and tol­er­ance to the drug.

The break­through has come as a re­sult of new re­search into the way mor­phine works.

While it’s long been known that opi­oids help to dull pain by act­ing on the neu­rons, the re­searchers found that in an­i­mal stud­ies the drugs do some­thing else pre­vi­ously un­known: they ac­ti­vate im­mune cells in the brain called glia.

‘‘ The glial cells see pain as some­thing they have to re­spond to, and when you in­tro­duce mor­phine they see it as some­thing for­eign and be­come even more ac­tive. They are too ea­ger to re­spond,’’ says Mark Hutchin­son, who is lead­ing the re­search.

The re­searchers iden­ti­fied a spe­cific re­cep­tor that mor­phine uses to ac­ti­vate glia — and found that AV411 can block that re­cep­tor so the im­mune cells don’t ‘‘ see’’ the mor­phine.

‘‘ AV411 blocks and re­verses mor­phine’s ef­fects on glia, while at the same time leav­ing the neu­rons alone so the mor­phine can still deaden them to pain,’’ Hutchin­son says.

In an­i­mals, the re­searchers found a link be­tween the ac­tive glia and the ‘‘ re­ward­ing’’ eu­phoric state that makes mor­phine plea­sur­able and ad­dic­tive. The more re­ward­ing a drug is, the more ad­dic­tive it is.

When re­searchers mea­sured the re­ward by mon­i­tor­ing the rats’ be­hav­iour and mea­sur­ing the lev­els of a re­ward chem­i­cal re­leased from the rats’ brains, they found that there was no re­ward in rats that had been given mor­phine along with AV411. ‘‘ AV411 abol­ishes the re­ward so our rats, and hope­fully peo­ple, won’t show de­pen­dence . . . if the drug is less re­ward­ing, you’re less likely to say ‘ That was fun, let’s do it again’,’’ Hutchin­son says.

As the glial cells be­come more ac­tive, more pain is ex­pe­ri­enced, coun­ter­act­ing the pur­pose of the drug, he says.

‘‘ So the mor­phine you were tak­ing for your pain can in some cases make that pain worse,’’ Hutchin­son says. ‘‘ If you had a cold virus, your im­mune sys­tem would be look­ing to at­tack it. In this case mor­phine is act­ing like a virus — it shouldn’t be there, and so im­mune cells in the brain keep get­ting more ac­tive to get rid of it, but they never can be­cause you are tak­ing it twice daily.’’

In the past when sci­en­tists have de­vel­oped stronger, more pow­er­ful opi­oid drugs, they have also made them more re­ward­ing. By block­ing the im­mune cells from be­com­ing ac­tive they could po­ten­tially com­bat that prob­lem, he says.

Larger-scale clin­i­cal tri­als are be­ing planned where pa­tients will be given AV411 on its own with­out other pain-killing med­i­ca­tion to see if it has an anal­gesic af­fect. More re­search will also be needed to see if Hutchin­son’s find­ings around ad­dic­tion and de­pen­dence hold true in hu­mans as well.

Ex­perts agree there is an ur­gent need for bet­ter drugs that tar­get the root causes of chronic or per­sis­tent pain. Last month an MBF Foun­da­tion-funded study run by the Pain Man­age­ment Re­search In­sti­tute at Syd­ney Univer­sity found that 3.2 mil­lion Aus­tralians suf­fer from chronic pain, with an an­nual price tag of more than $34 bil­lion. A third of those peo­ple are ex­pe­ri­enc­ing se­vere pain that causes sub­stan­tial dis­abil­ity — a re­cent study at the PMRI found they were more dis­abled than peo­ple with heart fail­ure, says PMRI di­rec­tor of re­search, pro­fes­sor Michael Cousins.

If in­deed the re­sults of the re­search do trans­late into a new breed of drugs it will be a wel­come ad­vance.

‘‘ Most of the drugs we have been us­ing pro­vide symp­to­matic re­lief for pain, but per­sis­tent pain has its own signs and symp­toms and ab­nor­mal­i­ties in the ner­vous sys­tem. There are quite marked changes that oc­cur in the nerves them­selves in the spinal cord and brain,’’ says Cousins, who is the im­me­di­ate past pres­i­dent of the Aus­tralian and New Zealand Col­lege of Anaes­thetists (ANZCA). ‘‘ We need to be get­ting at dis­ease pro­cesses with drugs that hit spe­cific tar­gets.’’

How­ever, there is some way to go be­fore we reach this goal.

‘‘ This is very in­ter­est­ing re­search but we don’t know yet how it fits in. It could be sev­eral years be­fore this re­searches the clinic,’’ Cousins says. ‘‘ We need de­fin­i­tive in­for­ma­tion about whether this im­pacts on tol­er­ance to the drug or whether it has anal­gesic ef­fects of its own. We still need to tease out how big a role the glia play in ad­dic­tion and tol­er­ance com­pared to the nerve cells,’’ Cousins says.

Roger Goucke, dean of ANZCA’s fac­ulty of pain medicine, also says that while it’s too early to tell what the re­sults will ul­ti­mately be, the re­search seems promis­ing.

‘‘ It’s a whole new area of pain ther­apy,’’ Goucke says. ‘‘ Mor­phine doesn’t work for all pain — and if you use it for a long time, you have to take more and more be­cause you be­come tol­er­ant to it.

‘‘ The glial cells ap­pear to be in­volved in chang­ing the mes­sage that the brain re­ceives, so if you can use the drugs to change the way that pain is re­ceived in the brain it will be a ma­jor ad­vance. This might be the first in a se­ries of drugs, with bet­ter ones com­ing down the line.’’

Around the world phar­ma­ceu­ti­cal com­pa­nies are de­vel­op­ing drugs aimed at more than a dozen dif­fer­ent ‘‘ tar­gets’’ to pre­vent or re­verse the process of per­sis­tent pain, Cousins says.

Re­searchers at the PRMI have also made promis­ing dis­cov­er­ies — they re­cently iden­ti­fied a mol­e­cule that blocks one of the ways in which pain sig­nals are trig­gered.

‘‘ Phar­ma­ceu­ti­cal com­pa­nies are de­vot­ing a lot of re­search and money to hit th­ese new tar­gets and that’s good for pa­tients,’’ Cousins says.

Pic­ture: Kelly Barnes

Pain: Re­searcher Paul Rolan says pa­tients given AV411 could lower their need for opi­ates

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