INTRODUCTION
* Resident of Internal Medicine, Medical Faculty of Brawijaya
University - Saiful Anwar General hospital Malang** Supervisor
,Professor and Consultant of Rheumatology imunlogy Division,
Internal Medicine Department Brawijaya University- Saiful Anwar
General hospital Malang
Dikara WS Maulidy*, Handono Kalim **
INTRODUCTIONKortikosteroid inhalasi merupakan terapi yang utama
pada pasien asma dan COPD, terlebih pada pasien yang rekurent
Sementara itu, Glukokortikoid oral juga dapat berkontribusi pada
dosis tertentu menjadi hyperglycemia/tolerasi glukosa terganggu dan
diabetes pada pasien yang memiliki risiko, konsentrasi di dalam
darah (sistemik) yang tercapai pada pasien amsa atau copd dengan
terpi ICS dianggap terlalu rendah untuk mempengaruhi glukosa plasma
pada kebanyakan pasien
However, a large nested case-controlled study, involving
patients treated with ICS for asthma or COPD, reported a 34%
increase in the incidence of diabetes mellitus over 5.5 years of
follow-up versus age-matched controls who were not treated with
ICS.The extensive clinical trial programme conducted for budesonide
provides a considerable pool of patient data from which to examine
the impact of ICS therapy on a variety of patient outcomes,
including the risk for diabetes mellitus.By contrast, two other
studies of ICS in elderly patients failed to demonstrate any
increased risk of diabetes related to ICS exposure.In a prospective
cohort study of US veterans over 1 year, ICS exposure was
associated with a dose-dependent increase in serum glucose
concentrations in patients with established diabetes mellitus, but
not in patients without diabetesSimilarly, in a small, prospective,
crossover study in patients with established type 2 diabetes
mellitus, glycosylated haemoglobin levels rose significantly after
6 weeks of treatment with inhaled fluticasoneTogether, these
observations suggest that ICS may exacerbate diabetes in asthma or
COPD, by increasing blood glucose levels in patients with
established diabetes mellitus. Their impact on incidence of
diabetes mellitus, however, remains uncertainThe present pooled
analysis was undertaken to determine whether ICS increases the risk
of new onset diabetes mellitus or hyperglycaemia among patients
with asthma or COPD treated with budesonide compared with those who
did not receive budesonide in the randomised controlled trials
MethodsThis study analysed data from all trials which used
inhaled budesonide, and were randomized, double blinded involved
patients 4 years of age, who had either asthma or COPD, had a
follow-up of more than 3 months (asthma) or >6 months (COPD) and
were fully completed by December 2010.Datasets6Trials involving
either placebo or active control therapiesnbwere included. This
comprised 26 double-blind, placebo-controlled trials of budesonide
or budesonide/formoterol in patients with asthma (included in the
primary asthma dataset) (online repository Table),34 double-blind
active controlled trials of budesonide or budesonide/formoterol in
patients with asthma (combined to give a total of 60 asthma trials
in the secondary asthma dataset), and 8 double-blind trials of
budesonidecontaining products in patients with COPD, of which 7
were placebo-controlled (included in the COPD dataset) (online
repository Table)Outcome variablesDiabetes mellitus cases were
identified as any adverse event (AE) or serious adverse event (SAE)
coded to the MedDRA dictionary (version 13) as the term Diabetes
mellitus (including subtypes); Diabetic ketoacidosis; Diabetic
hyperglycaemic coma or Diabetic hyperosmolar coma. Hyperglycaemia
cases were identified as any AE (serious or non-serious) coded to
the MedDRA dictionary (version 13) as the terms Hyperglycaemic
conditions NEC, Blood glucose increased, Carbohydrate tolerance
decreased, Glucose tolerance decreased, Glucose tolerance test
abnormal or Glycosylated haemoglobin increased. Thus, diabetes AEs
were defined as any new onset diabetes mellitus or worsening of
existing diabetes. Patients with existing diabetes mellitus were
not excluded, as the AEs were examined post randomization to either
ICS or non-ICS treatment.Statistical analysisThe risk of diabetes
mellitus/hyperglycaemia as an AE or SAE was compared between
patients assigned to budesonide or non-ICS treatments. KaplaneMeier
curves were generated to visually compare the time to the first
reported cases of diabetes mellitus/hyperglycaemia Aes between
treatment groups.Cox proportional hazards regression modelling,
both adjusted and not adjusted by study, was used to estimate the
relative risk of ICS on time to the occurrence of diabetes
mellitus/hyperglycaemia AesHazard ratios (HRs) and the associated
95% confidence intervals (CIs) were calculated from these models.In
the primary asthma dataset, a single trial, START,9 contributed the
majority of patients (n Z 7221). As a sensitivity analysis, the
overall RR was calculated for the START trial alone and for all
trials in this dataset excluding START.We also determined a
possible dose response by evaluating high versus low dose
budesonide. For the doseeresponse analysis in asthma, only trials
that contained a low-dose treatment arm as well as a high-dose
treatment arm were selected (14 trials), and for the budesonide vs
fluticasone comparison only trials involving both ICS were selected
(5 trials).We defined low dose as budesonide of 320 mg/day
delivered via Turbuhaler or pressurised metered-dose inhaler (pMDI)
or budesonide of 500 mg/day delivered as a nebulizing
suspensionHigh dose was defined as budesonide 640 mg/day via
Turbuhaler or pMDI or 1000 mg/day as a nebulizing suspensionFrom
the STAY trial,10 only adolescent and adult patients from the
budesonide/formoterol 160/9 mg/day and the 640 mg/day treatment
arms, respectively were included in the doseeresponse analysis
since in this study the children 4e11 years of age received only
half of these doses.The comparisons of high-dose vs. low dose
budesonide, and of budesonide and fluticasone, were performed using
a ManteleHaenszel approach stratified by study and adjusted for
treatment exposure on a subset of trials from the secondary asthma
dataset. For the doseeresponse analysis, only trials that contained
a low-dose treatment arm as well as a high-dose treatment arm were
analysedIn the COPD dataset, a doseeresponse analysis was conducted
on the 3 studies which included two different doses of a
budesonide/formoterol (640/18 mg and a 320/18 mg) using the
ManteleHaenszel approach stratified by study and adjusted for
exposure.In both the secondary asthma and COPD datasets, risk
factor analyses using linear-tailed restricted cubic splines in a
Cox regression were used to model and adjust for potential
non-linearities for age, body mass index (BMI) and baseline forced
expiratory volume in 1 s (FEV1) expressed as a percentage of
predicted normalFinally, as four studies in the COPD dataset
included the measurement of laboratory safety data, an additional
dataset was compiled consisting of all patients for whom a baseline
and end-of-treatment blood glucose evaluation was available. These
data were analysed to determine the mean change from baseline to
end-of-treatment glucose levels for ICS- and non-ICStreated
patients.As this was a retrospective review of results from a
number of clinical trials, no approval was requested from Research
Ethics Committees from those institutions where the data was
collected.Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Both
selective and non-selective cyclooxygenase (COX) inhibitors have
antipyretic, anti-inflammatory and analgesic effects and are widely
used in treating many painful conditions, including rheumatic
diseasesContrary to some clinical assumptions, gastrointestinal
risk is present at first dose with a non-selective NSAID, and
co-therapy with a proton pump inhibitor (PPI) does not guarantee
complete protectionCOX-2 selective NSAIDs, especially in
combination with a PPI, provide prophylaxis against NSAID
gastropathy
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Both conventional
NSAIDs and COX-2 inhibitors are associated with increased
cardiovascular risk [34-37].NSAIDs should be used at the lowest
effective dose for the shortest possible period of time in chronic
pain populationsParacetamolIt is often considered a first-line
approach to pain managementalthough there is a risk of hepatoxicity
at high dosesParacetamol was shown in one study to significantly
increase blood pressure in ambulatory patients with coronary artery
diseaseThe frequency of use of paracetamol has been independently
associated with a moderately increased risk of hypertension in
menSome evidence in the literature to suggest that paracetamol may
have an anti-inflammatory effect in patients with OA of the knee
Although earlier reports describe paracetamol as having no or
minimal anti-inflammatory effectsTramadolTramadol is considered a
weak opioid on the WHO pain ladder [59]Tramadols analgesic effect
derives from a combination of an agonist action at mu-opioid
receptors and inhibition of neuronal reuptake of serotonin (5-HT,
5-hydroxytryptamine) and norepinephrineTramadol has been shown to
decrease pain intensity in OA patients and to improve function;
active-controlled studies show that tramadol provides analgesic
benefits similar to diclofenac and superior to
paracetamolRecommended dosing should not exceed 400 mg/d, and
should be reduced or closely supervised in geriatric patients
(>75 years) and those with cirrhosis or renal dysfunction [30].
Tramadol has no known anti-inflammatory effects
OpioidsOpioids are effective in treating chronic pain but are
associated with side effect including nausea, constipation, and
somnolence.In summary, clinicians may be cautious in prescribing
opioids to treat OA or RA for clinical, legal, or public health
reasonsTricyclic AntidepressantsMechanisms, tricyclic
antidepressants (TCAs, e.g. amitriptyline, dothiepin, and
imipramine) inhibit serotonin and norepinephrine reuptake and
neuronal sodium channelsVarious tricyclic TCAs differ with regard
to their antinociceptive effects, and the non-serotoninergic
properties of TCAs are believed to substantially contribute to
these differencesTCAs provide significant pain relief in RA
patients versus placebo The use of TCAs in arthritis has found such
a wide distribution that it has been proposed that these agents
along with anticonvulsants should be described as pain-modifying
drugs.Tricyclic AntidepressantsTCAs offer arthritis patients an
analgesic benefit apart from their antidepressive effects. It has
been speculated that at least part of this benefit relates to
Simprovement of fatigue and sleep disordersTCAs are associated with
certain adverse events, which include sedation, dizziness, blurred
vision, constipation, and dry Smouth, which can be treatment
limitingCardiac toxicity is a concern with TCAs, and the NeuPSIG
guidelines (Neuropathic Pain Special Interest Group) recommend
prescribing TCAs with caution in patients with ischemic cardiac
disease or ventricular conduction abnormalitiesTricyclic
AntidepressantsSome TCAs, e.g. amitriptyline, are listed on the
recently revised Beers list (American Geriatrics Society) of
potentially inappropriate medication use in older adults with a
strong recommendation to avoid using them because they are highly
anticholinergic, sedating, and cause orthostatic
hypotensionAnticonvulsantssAnticonvulsants, e.g., gabapentin and
pregabalin, bind to the alpha2delta subunit of calcium channels and
modulate the release of neurotransmitters, including glutamate,
noradrenalin, and serotoniN, these agents may provide analgesic
relief for patients with central sensitization.However, the
mechanisms of action of these drugs are still poorly understood
While known to be effective analgesics for fibromyalgia, these
agents have not been studied in RA and OA populations.Serotonin
Norepinephrine Reuptake InhibitorsSerotonin norepinephrine reuptake
inhibitors (SNRIs), inhibit serotonin and/or norepinephrine
reuptake selectively, e.g., duloxetine and milnacipran. Overall,
SNRIs are better tolerated than TCAs but maybe less effective
analgesics; they are not recommended as first-line drugs for
analgesia in RA patients,A recent study found duloxetine was an
effective analgesic in patients with OA of the
kneeCorticosteroidsDue to their potent anti-inflammatory effects,
corticosteroids have been shown to be effective adjuvant analgesics
in a variety of painful rheumatic conditions, including RA and
other autoimmune disordersAccording to the NICE guidelines for RA,
patients with established RA should only continue long-term
treatment with glucocorticoids when the long-term complications of
glucocorticoid therapy have been fully discussed, and all other
treatment options (including biological drugs) have been
offeredTopical AgentsTopical products, such as lidocaine,
diclofenac, capsaicin, and salicylate, allow the patient to obtain
localized pain reliefThey are mainly used in combination with
systemic agents in the treatment of pain associated with rheumatic
disease.Topical diclofenac has been reported to be effective in
relieving pain caused by OA of the knee Topical NSAIDs do not
appear to have gastrointestinal adverse effects typical of oral
NSAIDs, but long-term studies are warranted to confirm this.Topical
AgentsOA treatment with topical lidocaine (5% lidocaine medicated
plaster) as monotherapy or add-on therapy resulted in significant
improvements in pain intensity [103-105], physical function, and
stiffness The use of topical capsaicin in OA is discussed
controversially: topical capsaicin is recommended for hand OA but
not for knee OA according to the ACR guidelines (American College
of Rheumatology) [106) whereas according to a recent review
concerns exist that capsaicin-induced nerve desensitization is not
fully reversible and that its autonomic nerve effects may increase
the risk of skin ulcers in diabetic patientsCOMBINATION
THERAPIES
The multimechanistic nature of OA, RA and most other chronic
pain indications suggests that a multimodal or combination approach
to analgesia may be appropriate to manage painCombining two
analgesic agents may allow for an additive or synergistic effect,
which can affect both the drugs analgesic efficacy as well as its
side effect profile [108, 109].Additive effects mean that the
effects of both agents are combined. Synergistic effects result in
a global effect that is greater than the sum of its parts.It is
important to understand that additive and synergistic effects may
imply side effects as well as efficacy.COMBINATION THERAPIES
Fixed-dose combination analgesic products offer certain
practical advantages, in that they are convenient, reduce the pill
burden, and may allow for lower dosages that might be insufficient
if the compounds were taken individuallyParacetamol is often a
component of combination products. A potential concern for such
products is that they may obscure the patients cumulative dose of
paracetamol (which should not exceed 4 g in healthy adultsTypical
combination products with paracetamol include opioid combinations
(codeine, tramadol, oxycodone, etc.)
COMBINATION THERAPIES
These products may be opioid sparing, because they provide
effective analgesia at lower opioid doses than opioids taken in
monotherapySynergistic analgesic benefits have been demonstrated
for the fixed dose combination tramadol/paracetamolPAIN CONTROL FOR
OA AND RA PATIENTSParacetamol is effective in treating certain
types of OA. The drug is considered as first-line treatment for
mild to moderate pain However, OA patients often prefer NSAIDS for
better pain relief [115]. NSAIDs are targeted therapy for pain
management in RA patients, but are not appropriate for long-term
disease controlFixed-dose combination products are seldom mentioned
in available OA and RA guidelines The NICE guideline initially
recommends paracetamol for all OA pain or topical NSAIDs for hand
and knee OA ahead of oral NSAIDs, COX-2 inhibitors or opioidsPAIN
CONTROL FOR OA AND RA PATIENTSTopical capsaicin should be
considered an adjunct to core treatment for hand and knee OA, and
intra-articular corticosteroid injections an adjunct in all OA
painThe OARSI guideline recommends the initial administration of
paracetamol for mild to moderate knee or hip OA, and topical NSAIDs
and capsaicin as adjuncts or alternatives to oral analgesics in
knee OA pain [119Weak opioids and narcotic analgesics can be
considered for refractory pain but stronger opioids should only be
used for severe pain in exceptional circumstances. The evidence
presented included fixed-dose combinations of opioids and
paracetamolPAIN CONTROL FOR OA AND RA PATIENTSBoth the NICE and
OARSI guidelines recommend the use of oral NSAIDs at the lowest
effective dose [50, 119]; long-term use should be avoided [119].The
recent ACR recommendations list topical capsaicin, topical NSAIDs,
oral NSAIDs (including COX-2 inhibitors) and tramadol for initial
pain treatment of hand OA, and advise against intra-articular
therapies and opioid analgesics [106].They recommend a similar
approach for knee and hip OA which includes paracetamol, oral
NSAIDs, tramadol, and intra-articular corticosteroid
injections.PAIN CONTROL FOR OA AND RA PATIENTSTopical NSAIDs are
recommended in knee OA (in particular for patients 75 years instead
of oral NSAIDs) but there is no recommendation in hip OATopical
capsaicin is not recommended in knee OA. Opioid analgesics are
strongly recommended only in symptomatic knee or hip OA following
insufficient response to both non-pharmacological and
pharmacological treatments and where patients are not suitable for
total joint arthroplasty.PAIN CONTROL FOR OA AND RA PATIENTSEarly
use of DMARDs in RA patients is of high importance [121, 122] ;
however, as pain is a major complaint in these patients, they
commonly take analgesics from the very beginning.According to
EULAR, symptomatic patients presenting with early arthritis should
be treated with NSAIDs after careful evaluation of
gastrointestinal, renal, and cardiovascular statusBSR guideline for
long-term RA management recommends a stepped approach with NSAIDs
co-prescribed with a proton pump inhibitor in the short termThe
NICE guideline suggests analgesics (for example paracetamol,
codeine or compound analgesics [=fixed-dose combinations]) to
potentially reduce the need for long-term NSAID or COX-2 inhibitor
treatmentPANEL CONSIDERATIONSWhile patient safety must be
paramount, clinicians must address chronic pain associated with OA
and RANot treating pain is not an optionPain guidelines must offer
clinicians better recommendations by taking into account the impact
of pain as well as the multiple mechanisms of RA and OA painIt is
particularly important that clinicians realize that arthritis pain
is not limited to nociception, but rather that non-nociceptive,
neuropathic, and central mechanisms are also important components
of OA and RA pain.PANEL CONSIDERATIONSNSAIDs and paracetamol are
commonly used, often recommended, and effective agents for the
management of pain. However, they are not without potential risks,
especially in the elderly and patients with renal,
gastrointestinal, or cardiovascular diseaseHigher doses of
paracetamol have been associated with liver toxicity, and since
paracetamol is a hidden ingredient in many over-the-counter
products and other combination products, the hepatic injury is of
particular concernFixeddose combination products including
paracetamol may offer the drug and the combined agent in relatively
low dosesPANEL CONSIDERATIONSFixed-dose combinations of paracetamol
provide a multimechanistic analgesic approach, which may be
appropriate to address the pain of OA and RA.Fixed-dose weak
opioid/paracetamol combination products have been shown to be
effective in managing various types of moderate to severe pain,
including the pain of OA and RA, with good tolerability.Tramadol,
because of its opioid and nonopioid mechanisms of action, appears
to be a promising opioid component in combinations for treating OA
and RA pain.PANEL CONSIDERATIONSArthritis-related pain is generally
characterized by flares of pain and periods of remission or
relatively diminished pain.To manage long-term arthritis pain a
low-dose fixeddose combination product should be considered as the
primary analgesic, providing safe and acceptable multimechanistic
pain relief.NSAIDs should only be used to manage acute flares
associated with inflammation.This is the reverse of a common
treatment regimen in which patients take chronic NSAID therapy and
use opioids to manage pain from flares.CONCLUSIONDespite the wealth
of analgesic options, treating arthritisrelated pain is still a
challenge for clinicians balancing efficacy with safety
aspects.Growing understanding of the multiple mechanisms of
arthritis pain has given clinicians greater appreciation for a
multimechanistic approach.The use of combination products, such as
tramadol and paracetamol for long-term pain management, is a good
option with proven evidence for relieving pain.NSAIDs are effective
pain relievers and helpful as add-on treatment for the painful
flares of arthritis.They are not safe at high doses or for
long-term use, especially in the frail and elderly. Revised
guidelines are required to help clinicians to better understand
safe, effective treatment options for arthritisrelated pain.THANK
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