Review

Treatment of osteoarthritis in
1. Introduction
2. Treatment of osteoarthritis in
patients with hypertension
3. Effects of paracetamol and
NSAIDs on cardiovascular risk
and blood pressure
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 11/13/14
hypertensive patients
Isla S Mackenzie† & Thomas M MacDonald
University of Dundee, Ninewells Hospital, Hypertension Research Centre and Medicines Monitoring
Unit, Level 7, Dundee DD1 9SY, UK
Importance of the field: Osteoarthritis and hypertension commonly co-exist.
Treatment of osteoarthritis in hypertensive patients is a therapeutic challenge
due to the adverse effects of some analgesics, especially non-steroidal anti-
inflammatory drugs (NSAIDs), on blood pressure. Even small drug-induced

rises in blood pressure due to therapy may significantly increase cardiovascular

4. Novel approaches to treating
risk in these patients if sustained over the long term. Patients treated with
osteoarthritis in hypertensive
patients
certain classes of antihypertensive agent may be at particular risk of deteri-
oration in blood pressure control with NSAID therapy. NSAIDs may also
5. Conclusions
increase cardiovascular risk due to mechanisms other than by raising
6. Expert opinion blood pressure.
Areas covered in this review: We discuss the management of osteoarthritis in
the hypertensive patient, review the evidence for the effects of paracetamol
and NSAIDs on blood pressure and discuss novel therapeutic strategies for
osteoarthritis that might diminish this problem. A literature search was
undertaken in PubMed including the years 1980 – 2009.
For personal use only.

What the reader will gain: Insight will be gained into the complexity of
treating patients with co-existent osteoarthritis and hypertension and into
possible new approaches to treating osteoarthritis symptoms effectively in
these patients while minimising any adverse impact on blood pressure control.
Take home message: There are ways to minimise the adverse impact of
treatment of osteoarthritis on blood pressure control in hypertensive patients.

Keywords: blood pressure, cyclo-oxygenase inhibiting nitric oxide donators (CINODs),

hypertension, nitric oxide, NSAIDs, osteoarthritis, paracetamol

Expert Opin. Pharmacother. (2010) 11(3):393-403

1. Introduction

Osteoarthritis and hypertension are common conditions that increase in prevalence

with age and often co-exist in the same patients. The predominant symptom of
osteoarthritis is joint pain. Most patients with significant osteoarthritis will even-
tually require intermittent or regular analgesia to control their symptoms. First-line
analgesic drug therapy is usually paracetamol (acetaminophen). If paracetamol
therapy does not give adequate pain relief, non-steroidal anti-inflammatory drugs
(NSAIDs) or opiate/opioid-like analgesics are used. The choice of painkiller for an
individual patient depends on tolerability and interactions with other medications
and underlying pre-existing medical conditions.
Hypertension is a recognised risk factor for cardiovascular events and treatment of
hypertension reduces cardiovascular risk [1]. Important considerations when choos-
ing therapy for osteoarthritis in a patient who also has hypertension include the
effects of the chosen analgesic on blood pressure, interactions with antihypertensive
agents and effects on overall cardiovascular risk. In this article, we consider the
evidence on treatment of osteoarthritis in hypertensive patients, concentrating on the
particular considerations when using NSAID therapy in these patients. Small
changes in blood pressure can have major effects on cardiovascular outcome. Having

10.1517/14656560903496422 © 2010 Informa UK Ltd ISSN 1465-6566 393

All rights reserved: reproduction in whole or in part not permitted
 Treatment of osteoarthritis in hypertensive patients
Article highlights.
. Osteoarthritis and hypertension commonly occur in the
same patients.
. NSAIDs and even paracetamol may worsen blood pressure
control.
. Even small increases in blood pressure may increase
cardiovascular risk significantly.
. Effects of NSAIDs on blood pressure may vary depending
on which antihypertensive therapies a patient is taking.
. Strategies to minimise adverse effects of NSAID therapy
on blood pressure include the use of novel agents such as
the cyclo-oxygenase inhibiting nitric oxide donors
(CINODs).
. Other potential novel agents for the treatment of
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 11/13/14
osteoarthritis.
This box summarises key points contained in the article.
a 5-mmHg lower usual systolic blood pressure is estimated to
reduce the risk of stroke by 40% and coronary heart disease by
25% [2,3]. Even small increases in blood pressure secondary to
chronic NSAID use can be important if sustained in the long
term. We also explore novel approaches to treating the pain
For personal use only.
and inflammation of osteoarthritis while trying to minimise
any additional cardiovascular risk or effects on blood pressure.
2. Treatment of osteoarthritis in patients with
hypertension
2.1Lifestyle changes in patients with osteoarthritis
and hypertension
Both osteoarthritis and hypertension can be improved to some
extent by lifestyle measures including exercise and weight
loss [4]. Exercise is recommended for any patient with oste-
oarthritis, whatever their level of disability [5]. Muscle-
strengthening exercises optimise joint support and ensure
good weight distribution when walking. Patients with osteo-
arthritis are advised to lose weight if they are overweight and
exercise can assist this process. Weight loss reduces the load
applied to the large weight-bearing joints and can slow the rate
of deterioration of osteoarthritis in joints such as the knee,
although there is less evidence that it directly helps the hip
joints and probably has little impact on osteoarthritis of
smaller joints such as in the hands. Similarly, both exercise
and weight loss lower blood pressure in hypertensive patients.
While short-term studies have suggested that there is approx-
imately a 1-mmHg reduction in blood pressure associated
with each 1-kg weight loss in overweight patients, a more
recent review suggests that longer-term effects might be more
modest, with decreases of 6.0 mmHg systolic blood pressure
and 4.6 mmHg diastolic blood pressure for a 10 kg of weight
loss [6]. The greatest benefit of exercise on blood pressure is
seen when patients who were previously sedentary take up
moderate exercise.
394 Expert Opin. Pharmacother. (2010) 11(3)
2.2Drug therapy in patients with osteoarthritis and
hypertension
The aim of drug therapy in osteoarthritis is to achieve
adequate analgesia to enable patients to continue with their
normal activities without experiencing pain and discomfort.
Simple analgesia using paracetamol as required is usually the
first step, introducing regular therapy as required. If paracet-
amol provides inadequate pain relief, an NSAID or opiate
analgesic is used. There is wide variability in analgesic response
to the different agents in different patients and the choice of
therapy in any individual will depend on cost, efficacy and
side-effect profile. Alternative therapies include topical
NSAIDs, which are useful when pain is limited to a small
number of joints and which may avoid some of the systemic
side effects of oral NSAIDs [7]. Maximum plasma NSAID
levels achieved by topical therapies are only around 15 – 20%
of those achieved with equivalent oral NSAIDs [8,9]. Other
topical therapies that may be of benefit to some patients with
osteoarthritis include capsaicin and rubefacients [10]. Intra-
articular corticosteroid injections may also be useful when
single joints are particularly problematic.
2.2.1 Paracetamol (acetaminophen)
Paracetamol is one of the most commonly used and widely
available analgesics. Although it is sometimes classified as an
NSAID, it differs in several ways and is therefore probably best
considered separately. Like the NSAIDs, it is believed to act by
inhibiting cyclo-oxygenase. However, unlike most of the other
NSAIDs, paracetamol mainly inhibits CNS prostaglandins
rather than those in the peripheral nervous system at usual
doses. It also has no significant effect on platelet function.
Paracetamol has good analgesic and antipyretic actions but
its anti-inflammatory actions are less marked than those of
the NSAIDs.
2.2.2 Non-steroidal anti-inflammatory drugs
NSAIDs inhibit the enzyme cyclo-oxygenase (COX), which
catalyses the conversion of arachidonic acid to prostaglandins
and prostacyclin. COX inhibition leads to a reduction in the
production of inflammatory prostaglandins and prostacyclin.
There are two isoforms of COX, the constitutive isoform
(COX-1), which is present in many tissues, and the inducible
isoform (COX-2), which is induced at sites of inflammation
and tissue injury. Inhibition of COX-2 is thought to be largely
responsible for the analgesic and anti-inflammatory effects of
NSAIDs, whereas inhibition of COX-1 has some unwanted
effects such as reduction in prostaglandins in the gastric
mucosa that protect against erosion. Different NSAIDs
have different degrees of inhibition of the two isoforms of
COX. They are broadly classed as the traditional NSAIDs
(non-selective) and the COX-2 selective inhibitors (coxibs),
although this distinction is by no means absolute as some of
the traditional NSAIDs are much more COX-2 selective
than others.

Although there is little doubt that NSAIDs provide good
analgesic relief for many patients, concerns have been raised
over their side effects. NSAIDs, including aspirin, as a group
are the most common drug-related cause of hospital admission
for adverse events in the United Kingdom [11]. Side effects of
NSAIDs include gastrointestinal haemorrhage, renal
impairment, fluid retention sometimes precipitating conges-
tive heart failure and elevated blood pressure. Patients taking
long-term NSAIDs may also have increased risk of thrombotic
events such as myocardial infarction and cerebrovascular
accidents. Current prescribing recommendations state that
NSAIDs should be used at as low an effective dose as possible
and that the need for long-term treatment should be reviewed
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 11/13/14
periodically. However, clinicians recognise that for many
patients with chronic pain due to arthritis, NSAIDs are highly
effective analgesics therefore the risk:benefit balance
is difficult.
2.2.3 Opiates and opioid-like analgesics
Opiate or opioid-like analgesics, either alone or in combina-
tion with paracetamol, are often used in patients in whom
NSAIDs are ineffective or contra-indicated. While they may
provide effective analgesia, side effects are common and
include constipation, nausea and confusion; there is also a
For personal use only.
risk of dependence in susceptible patients. Opiates are
not known to have a significant influence on blood
pressure chronically and will not be considered further in
this article.
3.Effects of paracetamol and NSAIDs on
cardiovascular risk and blood pressure
3.1 NSAIDs and cardiovascular risk
Much attention has focused on the adverse effects of NSAIDs
on cardiovascular risk in recent years [12]. Data suggesting an
increased cardiovascular risk associated with NSAIDs have
come from both epidemiological studies and randomised
clinical trials, often in other disease areas and using higher
than standard doses of NSAIDs. Although some of the
observational data are likely to be confounded by the fact
that some people who take chronic NSAID therapy have other
illnesses that may independently increase their cardiovascular
risk (e.g., rheumatoid arthritis), there are consistent signals of
increased risk of cardiovascular events associated with use of
NSAIDs from multiple studies. Studies to date have suggested
that the risk increases with higher baseline cardiovascular risk,
greater duration of use, dose and with differing dosing regimes
and relates to non-selective NSAIDs as well as COX-
2-selective NSAIDs. However, the COX-2 inhibitor volun-
tarily withdrawn from the market, rofecoxib, seems to be
associated with the highest relative risk of cardiovascular
disease when used at high doses, whereas naproxen seems
to have a much lower or neutral risk [13,14]; other NSAIDs
probably lie between these extremes. If an NSAID must be
Expert Opin. Pharmacother. (2010) 11(3)
Mackenzie & MacDonald
given to a patient with high cardiovascular risk, naproxen
(with proton pump inhibitor) is the current preferred ther-
apy [15]. Interactions with the antiplatelet effects of aspirin may
also be important in determining the risk in patients on
longterm antiplatelet therapy [16]. Ongoing large prospective
randomised clinical trials such as the Prospective Randomized
Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or
Naproxen (PRECISION) study will help to answer the
question of whether differences in cardiovascular risk exist
between some of the commonly used agents [17].
Hypertensive patients are already at increased baseline risk
of stroke, myocardial infarction and renal disease and, there-
fore, may be more susceptible to any adverse risk associated
with NSAID use. While it is important that we maximise our
understanding of the risk:benefit ratios in such patients, many
patients suffering from arthritis would rather accept a poten-
tial increase in risk of future cardiovascular events in return
for effective pain relief with NSAIDs. Ideally, however,
effective pain relief should be provided using the safest
possible medication.
3.2Effects of NSAIDs and paracetamol on blood
pressure
NSAIDs have been recognised as a contributory factor
to hypertension and resistant hypertension in national
hypertension treatment guidelines [18].
3.2.1 Observational data
Some observational data in humans have linked the use of
NSAIDs or paracetamol with higher rates of incident hyper-
tension. However, such data must be interpreted with caution
as people taking chronic painkillers may have underlying
illnesses that already put them at higher risk of developing
hypertension and all confounders may not have been taken
account of fully. In a prospective study of incident hyper-
tension in two cohorts of US women aged 51 – 77 years and
34 – 53 years, compared with non-use of analgesics, paracet-
amol use (> 500 mg daily) was associated with a relative risk of
developing hypertension of 1.93 [95% confidence interval
(CI) 1.30 – 2.88] in older women and 1.99 (95% CI
1.39 – 2.85) in younger women. Similarly, NSAID use
was associated with a relative risk of incident hypertension
of 1.78 (95% CI 1.21 – 2.61) in older women and 1.60 (95%
CI 1.10 – 2.32) in younger women. Aspirin was not associated
with increased risk [19]. However, a study in men showed no
association between development of hypertension and use of
NSAIDs, aspirin or paracetamol [20]. Another observational
study looked at the risk of developing hypertension in patients
taking COX-2 inhibitors. Patients taking rofecoxib had an
increased risk of developing new hypertension than patients
taking celecoxib, traditional NSAIDs or no NSAID. The risk
of developing hypertension with rofecoxib was higher in
patients with pre-existing chronic renal disease, liver disease
or congestive heart failure [21].
395
 Treatment of osteoarthritis in hypertensive patients
3.2.2 Mechanisms of increased blood pressure
NSAIDs have the potential to increase blood pressure acutely
by a combination of mechanisms (Figure 1) [22,23]. One of the
most important mechanisms is salt and water retention.
Inhibition of COX-mediated prostaglandin production in
the renal arteries reduces renal blood flow, decreasing the
glomerular filtration rate. This finding is seen with both
traditional non-selective and COX-2 selective NSAIDs.
This results in increased reabsorption of sodium in the
proximal tubules. Sodium and water retention may also be
exacerbated by increased anti-diuretic hormone (ADH)
(vasopressin) production and increased salt reabsorption in
the loop of Henle.
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Other mechanisms by which NSAIDs increase blood pres-
sure include vasoconstriction, which results in increased
peripheral vascular resistance. This may occur due to the
inhibition of vasodilatory prostaglandins [PGE2 and PGI2
(prostacyclin)] [24] and increased production of the potent
vasoconstrictor, endothelin-1 (ET-1) [25]. COX inhibition also
results in increased metabolites of arachidonic acid, some of
which may cause vasoconstriction. Activation of the renin–
angiotensin system may occur under some circumstances,
leading to further vasoconstriction, especially in patients
with low renin levels, such as the elderly. The effects of
For personal use only.
NSAIDs on blood pressure are thought to be reversible on
stopping therapy.
The effects of NSAIDs on the cardiovascular system
may be greater in some patients than others. Patients
with a history of cardiovascular disease or left ventricular
dysfunction are more likely to display symptomatic oedema
or other signs of heart failure due to salt and water
retention when exposed to NSAID therapy [26]. The pressor
effect of NSAIDs seems to be greater in patients who are
already hypertensive [27]. NSAIDs also interact with some
antihypertensive agents, counteracting or inhibiting their
effects [28]. Salt intake may also be important in deter-
mining the blood pressure effects of NSAIDs. Resistant
hypertension is thought to be largely a salt-dependent
condition and in a recent randomised, cross-over study in
patients with resistant hypertension, a lower sodium diet
(50 mmol/day) led to significant reductions in blood pres-
sure of 22.7 mmHg systolic and 9.1 mmHg diastolic blood
pressure compared to a higher sodium diet (250 mmol/
day) [29]. As one of the dominant mechanisms of blood
pressure increases in patients taking NSAIDs is thought to
be salt retention, strategies to reduce dietary salt intake
may be key.
Whether paracetamol affects blood pressure is more
controversial. Whereas some studies have suggested a similar
increase in blood pressure with paracetamol as with
some NSAIDs, others have suggested no significant
effect [19,20,27,30-32]. The salt content of some effervescent
preparations of paracetamol and other agents may contribute
to poor hypertension control [33]. In a study of 34 elderly
hypertensive patients with uncontrolled hypertension,
396 Expert Opin. Pharmacother. (2010) 11(3)
changing from an effervescent preparation of paracetamol
(containing 74 mmol/day sodium) to a tablet form (sodium
free) resulted in lower systolic and diastolic pressures,
13.1 mmHg (95% CI 11.9 – 14.3; p < 0.0001) and
2.5 mmHg (95% CI 2.1 – 2.9; p < 0.0001) lower respectively,
although this was an observational, non-randomised study [34].
3.2.3 Interventional studies
Several interventional studies have attempted to investigate
the effects of NSAIDs on blood pressure. However, some
of the clinical trial data on whether NSAIDs influence
blood pressure are difficult to interpret because of the lack
of placebo comparators and the predominance of small
and short-term studies in which blood pressure was not
always the primary outcome measure. Table 1 summarises
the interventional studies of the effects of NSAIDs on
blood pressure; these are discussed in more detail below.
In a randomised, controlled, cross-over study in healthy
female volunteers, short-term (1 week) administration of ibu-
profen 1200 mg daily did not influence mean 24-h ambula-
tory blood pressure [35]. However, effects may be different in
younger, healthy populations than in older patients with
other pre-existing conditions. Overall, according to data from
meta-analyses, most of the traditional and COX-2 selective
NSAIDs seem to increase blood pressure slightly. In a meta-
analysis by Pope et al., looking at the effects of traditional
NSAIDs on blood pressure in largely hypertensive patients,
the greatest increases in blood pressure were associated with
naproxen and indometacin. Ibuprofen, piroxicam, sulindac
and aspirin had negligible effects on blood pressure [36].
Another meta-analysis by Aw et al. looked at the different
effects of the traditional NSAIDs and the COX-2 selective
NSAIDs compared to placebo. The traditional NSAIDs as a
group raised systolic and diastolic blood pressures by 2.83 and
1.34 mmHg, respectively, while the COX-2 selective NSAIDs
elevated systolic and diastolic blood pressures by 3.85 and
1.06 mmHg, respectively, compared to placebo [37]. However,
on closer analysis, much of the increase in blood pressure with
the COX-2 inhibitor group was due to the greater effect of
rofecoxib than the other drugs in that class on blood pressure.
In a third meta-analysis by Johnson et al., which examined
the effects of traditional NSAIDs on blood pressure, as a
group, NSAIDs increased supine mean arterial pressure by
5.0 mmHg (95% CI 1.2 – 8.7 mmHg). Differences were seen
between individual NSAIDs, with piroxicam causing the
greatest increase in blood pressure (6.2 mmHg, 95% CI
0.8 – 11.5 mmHg) and sulindac and aspirin having the least
effects [38].
In a double-blind, randomised trial comparing the effects
of celecoxib, rofecoxib and naproxen on 24-h ambulatory
blood pressure in patients with type 2 diabetes mellitus,
osteoarthritis and hypertension, rofecoxib was the only agent
to induce a significant increase in 24-h systolic blood pressure
but some destabilisation of control occurred with all three
agents [39].

Arachidonic
acid
COX inhibition
Glomerular
blood flow
GFR
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 11/13/14
ADH
Metabolites of arachidonic acid
Figure 1. Mechanisms by which NSAIDs increase blood pressure. NSAIDs may cause salt and water retention and vasoconstriction by
a variety of mechanisms.
ADH: Anti-diuretic hormone; BP: Blood pressure; COX: Cyclo-oxygenase; ET-1: endothelin-1; GFR: Glomerular filtration rate; NaCl: Sodium chloride;
For personal use only.
NSAID: Non-steroidal anti-inflammatory drug; PG: Prostaglandin.
In another randomised trial in patients 65 years and above
with osteoarthritis who were also on antihypertensive therapy,
rofecoxib 25 mg daily significantly increased blood pressure
compared to celecoxib 200 mg daily [40]. It was hypothesised
that differences in the effects of celecoxib and rofecoxib on
blood pressure might be due to an aldosterone-mediated
effect, with rofecoxib competing with aldosterone for meta-
bolism by cytosol reductase, but further experimental work
failed to find any difference between the effects of the two
drugs on aldosterone levels [41]. Furthermore, in a randomised,
controlled trial comparing the effects of lumiracoxib and
ibuprofen on blood pressure in patients with controlled
hypertension, patients treated with lumiracoxib had signifi-
cantly lower blood pressures than those treated with
ibuprofen [42].
3.2.4Interactions with antihypertensive therapies
NSAIDs may counteract the effects of antihypertensive
therapy by the mechanisms listed above. However, there
may be a greater interaction with certain classes of antihy-
pertensive agent. In a study of celecoxib 200 mg daily versus
rofecoxib 25 mg daily in patients with hypertension and
osteoarthritis, there was no significant increase in blood
pressure with either coxib in those patients taking diuretics
or calcium channel blockers, while there was a significant
increase in blood pressure and peripheral oedema with
Expert Opin. Pharmacother. (2010) 11(3)
Mackenzie & MacDonald
COX PGE2
prostacyclin (PGI2)
(NSAID)
Reabsorption of NaCl
Salt + BP
water
retention
Vasoconstriction
ET-1
Vasodilatory
PGs
rofecoxib only in those patients taking angiotensin convert-
ing enzyme (ACE) inhibitors or beta-adrenoceptor antago-
nists [43]. In the meta-analysis by Johnson et al. described
above, it was noted that NSAIDs antagonised the antihy-
pertensive effects of beta blockers more than vasodilators or
diuretics [38]. In another study, elderly patients with con-
trolled hypertension taking amlodipine or enalapril were
treated with indometacin and placebo for 3 weeks each in
a randomised, double-blind cross-over study. Indometacin
significantly raised blood pressure only in those patients
taking enalapril. The blood pressure was 10.1/4.9 mmHg
higher in the enalapril-treated group than in the amlodipine-
treated group during the indometacin treatment period [44].
However, in a study of celecoxib versus placebo in patients
taking lisinopril for hypertension, there was no effect of
celecoxib compared to placebo on 24-h ambulatory blood
pressure [45].
In one prospective trial, 88 hypertensive patients were
divided into two groups: those taking NSAIDs for osteoar-
thritis and those on no NSAIDs. The group taking NSAIDs
was further divided into those taking amlodipine and those
taking lisinopril/hydrochlorothiazide combination therapy.
They were randomised to receive either ibuprofen or pirox-
icam, then paracetamol, then the assigned NSAID (ibuprofen
or piroxicam) again and blood pressure responses were
measured. In the lisinopril/hydrochlorothiazide group, both
ibuprofen and piroxicam raised blood pressure by 7.7 – 9.9%
397
 Treatment of osteoarthritis in hypertensive patients

Table 1. Meta-analyses and selected interventional studies of the effects of NSAIDs on blood pressure.

Author [ref. no.] Patient group Methodology NSAIDs studied Main results

Pope et al. [36] Largely hypertensive Meta-analysis Traditional NSAIDs Naproxen and indometacin
patients caused greatest increases in
blood pressure
Ibuprofen, piroxicam, sulindac
and aspirin had negligible effects
Johnson et al. [38] Various Meta-analysis Traditional NSAIDs Mean increase in supine MAP of
5.0 mmHg
Piroxicam greatest effect,
sulindac and aspirin least effects
Aw et al. [37] Various Meta-analysis Traditional NSAIDs and Traditional NSAIDs: mean
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COX-2 selective increase in SBP of 2.83 mmHg

McKenney et al. [35] Healthy female
volunteers
Sowers et al. [39] Hypertension,
osteoarthritis and
type 2 diabetes mellitus
Whelton et al. [43] Osteoarthritis, on
For personal use only.
NSAIDs and DBP of 1.34 mmHg and
COX-2 selective NSAIDs - mean
increase in SBP of 3.85 mmHg
and DBP 1.06 mmHg (mainly due
to rofecoxib effects)
Randomised, Ibuprofen No change in mean ABPM with
controlled, cross-over ibuprofen 1200 mg
trial
Double-blind Celecoxib, rofecoxib, Rofecoxib increased 24-h SBP
randomised trial naproxen
Randomised trial Celecoxib, rofecoxib Rofecoxib 25 mg increased blood

antihypertensive pressure compared to celecoxib

therapy, age ‡ 65 years 200 mg
MacDonald et al. [42] Patients with controlled Randomised Lumiracoxib, ibuprofen Lumiracoxib resulted in lower
hypertension controlled trial blood pressures than ibuprofen

ABPM: Ambulatory blood pressure monitoring; DBP: Diastolic blood pressure; MAP: Mean arterial pressure; NSAIDs: Non-steroidal anti-inflammatory drugs;
SBP: Systolic blood pressure.

above baseline in the first treatment period and by 7.0 – 7.7%
in the second NSAID treatment period, whereas paracetamol
raised it much less (0.3 – 0.9% above baseline) (p < 0.001 for
all results). However, in the amlodipine group, none of
ibuprofen, piroxicam or paracetamol raised blood pressure
significantly. Blood pressure in the control group did not
change [31].
Further work is necessary to fully understand the
interactions of NSAIDs with the different classes of anti-
hypertensive agent. However, the different mechanisms of
action of the various antihypertensive agents may exp-
lain why the interaction with NSAIDs on blood pressure
lowering effect is generally stronger with some agents
than with others. For example, the effects of ACE inhi-
bitors on blood pressure can be diminished if a high-
sodium diet is consumed, while the effects of calcium
channel blockers are largely unaffected by sodium status.
Therefore, one could postulate that the inhibition of renal
prostaglandins by NSAID and resultant sodium retention
might particularly counteract the antihypertensive effects of
ACE inhibitors.
4. Novel approaches to treating osteoarthritis
in hypertensive patients
4.1 Cyclo-oxygenase inhibiting nitric oxide donators
The cyclo-oxygenase inhibiting nitric oxide donators
(CINODs) (Figure 2) are a new class of drug developed in
recent years with a potential for use in treating osteoarth-
ritis [46]. The CINODs combine NSAIDs chemically with a
nitric oxide (NO) moiety [47] forming a new single chemical
entity. The NO attached to a linking molecule is cleaved from
the NSAID in vivo. The NO-donating group and linking
molecule then circulate allowing sustained and controlled
enzymatic release of NO to the tissues and avoiding the rapid
release of NO that is seen with some other agents such as
nitrates [48]. NSAIDs that have been linked to NO moieties in
this way include aspirin, diclofenac, flurbiprofen, ibuprofen
and naproxen [49]. In several different animal models of
inflammation, CINODs exert similar or greater anti-
inflammatory actions than their parent NSAIDs [50,51]. For
example, NO-aspirin lowers levels of the inflammatory cyto-
kine interleukin-1b more than standard aspirin [52]. In a

398 Expert Opin. Pharmacother. (2010) 11(3)


CINODs
NSAID NO
Analgesic Vasodilatation
Anti-inflammatory Inhibition platelet aggregation
Salt and water retention Gastro-protection
Vasoconstriction
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BP
Figure 2. Cyclo-oxygenase inhibiting nitric oxide (NO) dona-
tors (CINODs). CINODs combine a parent NSAID with an NO
moiety. The NO is released slowly via an esterase in the plasma. In
clinical trials to date, CINODs have been as effective as their parent
molecules in analgesic efficacy and have shown some gastro-
protective properties. They may also have more beneficial effects
For personal use only.
on blood pressure than their parent NSAIDs.
BP: Blood pressure; NSAID: Non-steroidal anti-inflammatory drug.
human study of dental pain, naproxcinod (NO–naproxen)
demonstrated similar analgesic efficacy as equimolar doses
of its parent NSAID, naproxen [53] and analgesic efficacy
has also been demonstrated in studies in patients with
osteoarthritis [54,55].
Although originally designed to reduce the risk of gastro-
intestinal haemorrhage compared to conventional
NSAIDs [56], a further advantage of the CINODs is their
relatively favourable effects on blood pressure, which could be
particularly useful when treating patients with both osteoar-
thritis and hypertension. NO is an endogenous vasodilator
that also inhibits platelet aggregation, and drugs releasing NO,
such as the nitrates, lower blood pressure [57]. Conversely,
inhibition of NO production increases blood pressure [58].
Several of the CINODs have effects on vascular tone or blood
pressure in animal studies. Both NO–flurbiprofen and NO–
aspirin cause NO-mediated vasorelaxation of rat aortic rings
in vitro, although no significant changes in blood pressure
were seen when these compounds were administered intrave-
nously to anaesthetised rats [59]. In a rat model of induced
hypertension (two-kidney, one-clip model), NO–naproxen
(naproxcinod) reduced systolic blood pressure compared to
vehicle or naproxen after 3 weeks [60]. In another study,
naproxen, naproxcinod or placebo was administered to
rats for 4 weeks. The blood pressure was higher in the
naproxen-treated rats than in those treated with naproxcinod
or placebo. When some of the rats were pre-treated with
Expert Opin. Pharmacother. (2010) 11(3)
Mackenzie & MacDonald
the NO synthase inhibitor, NG-nitro-L-arginine methyl ester
(L-NAME) to cause hypertension, naproxen therapy increased
the blood pressure further while naproxcinod reduced the
blood pressure [61].
In humans, effects of CINODs on blood pressure and
vascular tone are not yet well established. However, some data
are available on the effects of naproxcinod, the CINOD at the
most advanced stage of clinical development, on blood pres-
sure. In a study in patients with osteoarthritis of the knee given
6 weeks of therapy with NSAID or CINOD, there were trends
towards reductions in systolic and diastolic blood pressures
with naproxcinod therapy (375 mg or 750 mg b.d., but not
125 mg b.d.), while there were trends towards increased blood
pressure in patients treated with naproxen (500 mg b.d.) or
rofecoxib (25 mg o.d.) [54]. The 375 mg and 750 mg b.d. doses
of naproxcinod provided equivalent pain relief to the rofe-
coxib. In another study, patients with osteoarthritis of the hip
or knee were randomised to receive one of three different doses
of naproxcinod, rofecoxib 25 mg o.d. or placebo for
6 weeks [55]. Naproxcinod provided effective pain relief
compared to placebo. All three doses of naproxcinod
(750 mg o.d., 750 mg b.d., 1125 mg b.d.) decreased mean
systolic blood pressure significantly compared to rofecoxib
therapy but not to placebo. Naproxen was not included as a
comparator in this study.
In addition, a recent clinical study compared the effects of
naproxcinod with naproxen and placebo on blood pressure in
916 patients with osteoarthritis. Naproxcinod 750 mg b.d.
reduced blood pressure compared to naproxen 500 mg b.d.
(p < 0.02) and naproxcinod showed similar changes in
diastolic blood pressure to placebo. In 207 hypertensive
patients treated with renin–angiotensin system blocking
agents with or without diuretics, naproxcinod 750 mg b.d.
therapy resulted in a 6.5 mmHg lower systolic blood pressure
than therapy with naproxen 500 mg b.d. (p < 0.02) [62].
Further studies will be needed to accurately assess the effects
of the CINODs on blood pressure in patients with hyper-
tension and to compare them to the actions of their parent
NSAIDs. It is not yet known whether the addition of the NO
moiety in the CINODs may reduce cardiovascular risk
associated with NSAIDs.
4.2Other novel approaches to treating osteoarthritis
in hypertensive patients
Numerous other agents have shown early promise in the
treatment of aspects of the pathogenesis of osteoarthritis, but
whether they would have significant effects on blood pres-
sure and cardiovascular risk when used clinically remains
unclear. Examples of possible future treatments include
selective matrix metalloproteases (MMP)-13 inhibitors [63],
curcumin and resveratrol, which target the nuclear factor
kappa-B signalling pathway [64], and fibroblast growth
factor 2, which may delay cartilage degradation [65]. These
agents are still at the early stages of investigation and
399
 Treatment of osteoarthritis in hypertensive patients
their potential places in the therapy of osteoarthritis are
not known.
5. Conclusions
Treatment of osteoarthritis in the hypertensive patient
requires an understanding of the potential adverse effects of
the various commonly used analgesics. In particular, the
possible adverse effects of NSAIDs on cardiovascular risk in
general and also more specifically on blood pressure need to be
considered. Newer agents such as the CINODs that release
NO show some promise in minimising the impact of NSAID
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Dalhousie University on 11/13/14
therapy on destabilisation of blood pressure but further studies
in humans are needed.
6. Expert opinion
Osteoarthritis and hypertension exist so commonly in the
same patients that it is almost surprising that we do not yet
have a combined preparation to treat both conditions. Perhaps
that is what we should be aiming for in the future. Meanwhile,
we need to achieve adequate pain control to allow patients to
enjoy their lives, while minimising any exposure to risk from
For personal use only.
their analgesic agent – either due to direct effects on blood
pressure or due to increases in cardiovascular risk due to
other mechanisms.
The ideal analgesic for use in patients with both osteoar-
thritis and hypertension would be one that provided good pain
relief, reduced any inflammation, had a neutral effect on (or
even lowered) the blood pressure and did not adversely
counteract the effects of any antihypertensive drugs the patient
was taking. It would also have an advantageous or neutral
effect on cardiovascular risk. One NSAID that seemed to show
promise in coming close to this ideal, at least in terms of
pain relief and blood pressure effects, was lumiracoxib,
but this was later withdrawn from the market due to
possible hepatotoxicity.
At present, much of our evidence on the effects of para-
cetamol and NSAIDs on blood pressure is of limited quality as
it was derived from observational studies, studies not specif-
ically designed to look at changes in blood pressure or studies
in which the methods of measurement of blood pressure were
not clearly defined and properly validated. Likewise much of
the evidence regarding cardiovascular risk attributed to
NSAID therapy comes from epidemiological studies or ran-
domised trials in specific conditions using non-standard doses
of NSAIDs. Until we have further data from long-term
prospective studies comparing the risks of different NSAIDs
in patients who take them chronically for conditions such as
osteoarthritis, uncertainty will remain over their relative
influences on cardiovascular disease risk. To date, the safest
approach is probably that recommended by several national
guidelines – to start with paracetamol therapy and only move
to NSAID therapy if pain is inadequately controlled. In those
400 Expert Opin. Pharmacother. (2010) 11(3)
patients at highest risk of cardiovascular events, earlier use of
opiate or opioid-like analgesics to minimise NSAID use might
be appropriate – although opiates come with their own set of
side effects. To date, naproxen has the best cardiovascular
safety record. Therefore, if use of NSAID is felt to be essential
in a patient with high cardiovascular risk, current evidence
suggests that naproxen should be the NSAID of choice,
used along with a proton pump inhibitor to reduce risk
of gastrointestinal bleeding. Careful management of cardio-
vascular risk factors should also be employed in these
patients, with attention to lifestyle factors such as smoking,
lipid-lowering therapy and glucose control.
There are differences between the effects on blood pressure
and cardiovascular risk of the different available NSAIDs.
Rofecoxib, which was withdrawn from the market several
years ago, probably had a more adverse effect on blood
pressure and cardiovascular risk than agents that remain
on the market now. Apart from rofecoxib, there is little
evidence that the remaining COX-2 selective inhibitors
behave differently from the traditional NSAIDs in terms
of effects on blood pressure. With the currently available
NSAIDs, we probably should accept that most of them are
likely to raise the blood pressure by a few mmHg and that
aggressive blood pressure lowering therapy will be necessary
alongside their arthritis therapy. Current data suggests that
the best first-line choice of antihypertensive agent for patients
taking NSAID may be calcium channel blocker. However,
the majority of patients with hypertension require more than
one therapy to achieve target blood pressure; therefore,
interactions between other antihypertensive therapies and
NSAIDs are almost inevitable in these patients. Dietary
salt restriction may be an important aid in limiting any
blood pressure effects of NSAID and is also useful in its own
right in the management of patients with resistant hyper-
tension. Although there is some antagonistic interaction
between diuretic therapy, which increases sodium loss, and
NSAID therapy which increases sodium retention, many
patients are likely to be taking both medications concur-
rently. Perhaps increased diuretic therapy might be the best
way to manage hypertension in these patients. Medications
such as spironolactone and amiloride can produce good
results in patients with salt-driven hypertension although
caution should be employed in using diuretic therapy, start-
ing at a low dose and increasing the dose slowly. It would be
useful to gather further prospective data on blood pressure
and cardiovascular effects of the most commonly used
NSAIDs in the older population with co-existing hyperten-
sion and osteoarthritis and also to study further interactions
with various antihypertensive therapies.
For patients with pre-existing hypertension, the possibility
of giving NSAID therapy without a concomitant increase in
blood pressure or cardiovascular risk would represent a major
advance in therapy. Therefore, drugs such as the CINODs
may be an exciting development in this field, if further data
show that they either have a neutral effect or even lower the

blood pressure. Of course, outcome data on these agents are a
long way in the future, and outcome data on other NO donors
such as the nitrates have been disappointing with no apparent
reduction in cardiovascular events or mortality. We await
further data on blood pressure effects of the CINODs with
great interest. Meanwhile, the choice of therapy for patients
with osteoarthritis must be based on individual preference
while avoiding drugs known to present higher risks than
similar alternatives.
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IS Mackenzie works on a large Pfizer-funded study of NSAID
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Affiliation
Isla S Mackenzie† MBChB PhD FRCP Edin &
Thomas M MacDonald BSc MD FRCP FESC
FISPE FBPharmacolS
†
Author for correspondence
University of Dundee,
Ninewells Hospital,
Hypertension Research Centre and
Medicines Monitoring Unit,
Level 7, Dundee DD1 9SY, UK
Tel: +44 1382 632575; Fax: +44 1382 740209;
E-mail: i.s.mackenzie@dundee.ac.uk
403