Dikara WS Maulidy*, Handono Kalim **

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

INTRODUCTION
Kortikosteroid 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 diabetes
Similarly, 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
fluticasone

 Together, 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 uncertain
The 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

Methods

Datasets

This 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.

 Trials 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 variables
Diabetes 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 analysis
The 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 Aes
Hazard 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
suspension
High dose was defined as budesonide 640 mg/day via
Turbuhaler or pMDI or 1000 mg/day as a nebulizing suspension
From 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 analysed
In 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 nonlinearities for age, body mass index (BMI) and baseline forced
expiratory volume in 1 s (FEV1) expressed as a percentage of
predicted normal
Finally, 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-oftreatment blood glucose evaluation was available. These data were
analysed to determine the mean change from baseline to end-oftreatment 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 diseases
Contrary 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
protection
COX-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 populations

Paracetamol
It is often considered a first-line approach to pain managementalthough
there is a risk of hepatoxicity at high doses
Paracetamol was shown in one study to significantly increase blood
pressure in ambulatory patients with coronary artery disease
The frequency of use of paracetamol has been independently associated with a
moderately increased risk of hypertension in men
Some 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 antiinflammatory effects

Tramadol
Tramadol 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, 5hydroxytryptamine) and norepinephrine
Tramadol 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 paracetamol
Recommended 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

Opioids
Opioids 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 reasons

Tricyclic Antidepressants
Mechanisms, tricyclic antidepressants (TCAs, e.g. amitriptyline,
dothiepin, and imipramine) inhibit serotonin and norepinephrine
reuptake and neuronal sodium channels
Various tricyclic TCAs differ with regard to their antinociceptive effects,
and the non-serotoninergic properties of TCAs are believed to
substantially contribute to these differences
TCAs 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 Antidepressants
TCAs 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 disorders
TCAs are associated with certain adverse events, which include
sedation, dizziness, blurred vision, constipation, and dry Smouth,
which can be treatment limiting
Cardiac 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 abnormalities

Tricyclic Antidepressants
Some 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 hypotension

Anticonvulsantss
Anticonvulsants, 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 Inhibitors
Serotonin 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 knee

Corticosteroids
Due 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 disorders
According 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 offered

Topical Agents
Topical products, such as lidocaine, diclofenac, capsaicin, and
salicylate, allow the patient to obtain localized pain relief
They 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 Agents
OA 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 patients

COMBINATION 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 pain
Combining 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 individually
Paracetamol 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 adults
Typical 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 monotherapy
Synergistic analgesic benefits have been demonstrated for the fixed
dose combination tramadol/paracetamol

PAIN CONTROL FOR OA AND RA

PATIENTS
Paracetamol 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 control
Fixed-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 opioids

PAIN CONTROL FOR OA AND RA

PATIENTS
Topical capsaicin should be considered an adjunct to core treatment for
hand and knee OA, and intra-articular corticosteroid injections an adjunct in all
OA pain
The 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 [119
Weak 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
paracetamol

PAIN CONTROL FOR OA AND RA

PATIENTS
Both the NICE and OARSI guidelines recommend the use of
oral NSAIDs at the lowest effective dose [50, 119]; longterm 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 intraarticular 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

PATIENTS
Topical NSAIDs are recommended in knee OA (in
particular for patients 75 years instead of oral NSAIDs)
but there is no recommendation in hip OA
Topical 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

PATIENTS
Early 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 status
BSR guideline for long-term RA management recommends a stepped approach
with NSAIDs co-prescribed with a proton pump inhibitor in the short
term
The 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 treatment

PANEL CONSIDERATIONS
While patient safety must be paramount, clinicians must
address chronic pain associated with OA and RANot treating
pain is not an option
Pain guidelines must offer clinicians better recommendations
by taking into account the impact of pain as well as the
multiple mechanisms of RA and OA pain
It is particularly important that clinicians realize that arthritis
pain is not limited to nociception, but rather that nonnociceptive, neuropathic, and central mechanisms are also
important components of OA and RA pain.

PANEL CONSIDERATIONS
NSAIDs 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 disease
Higher 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 concern
Fixeddose combination products including paracetamol may offer
the drug and the combined agent in relatively low doses

PANEL CONSIDERATIONS
Fixed-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 CONSIDERATIONS
Arthritis-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.

CONCLUSION
Despite 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
YOU