Combination Rx for OA should be considered more often

[Guest guest]

Jan 12, 2004

Combination Rx for OA should be considered more often

Raritan, NJ - A new study has shown that adding a tramadol/acetaminophen

combination pill to a COX-2 inhibitor can effectively control pain in

patients with osteoarthritis (OA) in whom monotherapy with a COX-2 inhibitor

is inadequate.

Dr Emkey (Radiant Research/Reading, Wyomissing, PA) and colleagues

from Ortho McNeil Pharmaceuticals, which markets a tramadol/acetaminophen

product, Ultracet®, report their findings in the January 2004 issue of the

Journal of Rheumatology [1].

In an accompanying editorial [2], Dr Roy D Altman (University of California,

Los Angeles) says there is an overreliance on monotherapy in OA and that

many patients do not have their pain adequately controlled by just 1 drug.

" Should the combination of analgesics be considered more often? " he wonders.

Significant improvements seen in some outcome measures, but not all

Emkey et al randomized 307 patients with OA whose pain was not adequately

controlled by a stable dose of a COX-2 inhibitor (either celecoxib 200

mg/day or more or rofecoxib 25 mg/day or more) to either Ultracet (tramadol

37.5 mg/acetaminophen 325 mg) or placebo in addition for a total of 13

weeks.

Significant improvements in visual-analog-scale (VAS) scores for pain relief

were found among those taking the combination pill in addition to the COX-2

inhibitor, compared with those taking the COX-2 inhibitor plus placebo. The

active treatment group also had significant improvements in WOMAC OA Index

physical function and Medical Outcome Study Short Form-36 role-physical

measures. Other components of the WOMAC score or SF-36 score were not

significantly different between the 2 groups.

Efficacy measures which showed significant differences between active and

placebo groups

" Results from this study support the use of

tramadol-37.5-mg/acetaminophen-325-mg combination tablets as adjunctive

therapy for OA pain when COX-2 selective NSAID therapy alone is

insufficient, " say Emkey et al. These findings reinforce a previous study

that showed that tramadol/acetaminophen is effective as add-on therapy in OA

patients with pain inadequately controlled by an NSAID, they note.

They add that the American College of Rheumatology states that a combination

of complementary analgesic agents or substitution of an alternative

pharmacological agent should be considered for subjects who do not receive

adequate relief from monotherapy.

Without specific guidance, patients will medicate themselves

In his editorial, Altman notes that without specific guidance from health

professionals, patients experiencing persistent or breakthrough OA pain

while on monotherapy will medicate themselves, often with worrying

consequences. For example, they may use more than 1 NSAID, thereby

increasing the risk of gastropathy; they may add an NSAID to a COX-2

inhibitor, thereby negating the reduced risk of GI-tract adverse events; or

they may unknowingly take a number of products containing acetaminophen,

placing them at risk for hepatic injury if they consume more than the

recommended dose of 4 g/day.

" Because the literature is not adequate, guidance documents fail to

emphasize combination therapy. "

" Considering the prevalence of OA and the frequency of inadequate pain

relief with initial therapy, it is reasonable to suspect that NSAID

combinations and inadvertent analgesic dosing caused by self-medication

contribute to morbidity and mortality, " he notes.

Altman told rheumawire that although many physicians do advise patients on

combination therapy and there is an increasing effort to make doctors more

aware of treating pain, " because the literature is not adequate, guidance

documents fail to emphasize combination therapy. "

Tolerability of combination: would acetaminophen alone be sufficient?

In their paper, Emkey et al say the tramadol/acetaminophen combination

showed better tolerability than some opioids in previous evaluations. Altman

says that, in terms of tolerability, " tramadol offers advantages over

opiates such as codeine, propoxyphene, oxycodone, and hydrocodone. " But he

adds it is worth noting that rates of many adverse events were significantly

higher in the tramadol/acetaminophen/COX-2 group in this study: somnolence

(6.5% vs 0.7% in COX-2/placebo group); nausea (4.6% vs 0.7%); constipation

(3.3% vs 0%); fatigue (2.6% vs 0%); and vomiting (1.3% vs 0%).

" These GI and CNS [central-nervous-system]-related adverse events are more

likely to result from the opiatelike tramadol than from use of

acetaminophen, " Altman suggests, and he wonders whether just adding

acetaminophen to an NSAID (COX-2 specific or otherwise) would be sufficient.

" My own preference is to use acetaminophen with tramadol or acetaminophen

with a COX-2 specific inhibitor. . . . I might then move to a combination of

all 3. "

He told rheumawire: " My own preference is to use acetaminophen with tramadol

or acetaminophen with a COX-2 specific inhibitor, depending on the severity

of symptoms. I might then move to a combination of all 3. "

He says Ultracet is the only tramadol/acetaminophen combination product

available in the US. " The same benefit can be achieved by the less expensive

generic products separately, [but] the benefit of the combination is the

dosing of tramadol37.5 mgin contrast to tramadol alone50 mg. Patients,

particularly the elderly, often have side effects to the 50-mg dose when

starting therapy. " He adds: " I often start patients with half a 50-mg dose

for the first 3 days, then titer the dose up to tolerance/benefit/maximum

dose. "

In conclusion, Altman says, ''Emkey and colleagues have provided us with

valuable data on what to expect when adding tramadol/acetaminophen when

COX-2 therapy is not adequate. These are the type of data we need to

confront the clinical realities of OA management. " Similar studies on the

safety and efficacy of other variations of combination therapy " will enhance

our ability to provide more optimal pharmacological management of the pain

of OA. "