Assignment

Santos, Kirsten Gail

Busse JW, Wang Li, Kamaleldin M, et al. Opioids for Chronic Noncancer Pain: A

Systematic Review and Meta-analysis. JAMA. 2018; 320 (23): 2448-2460. Doi:

10.1001/jama.2018.18472

Purpose:

Many people in the United States are living with chronic pain. Most were prescribed

with opioid medications as pain management. The effect of opioids on chronic non-cancer pain

is uncertain, but there are harm associated with opioid use, such as diversion, addiction,

overdose, and death. This study aims to systematically review and make a meta-analysis of

randomized clinical trials (RCTs) of opioids for chronic non-cancer pain using the more recent

data.

Experimental Methods:

These systematic review and meta-analysis used DistillerSR,

online systematic review software, to facilitate literature screening

and included trials which had patients with chronic non-cancer pain,

had randomized them to an oral or transdermal opioid vs. non-opioid

control and conducted follow-up for at least 4 weeks. And the

primary outcomes observed are pain, physical functioning and

vomiting incidence. Risk bias was assessed using a modified Cochrane

risk of bias instrument. All continuous outcome measures reported by

more than 1 study were pooled and the weighted mean difference and

the risk difference of achieving the minimally important difference

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Santos, Kirsten Gail

were calculated. They used the pooled mean difference to estimate

the mean in the treatment group and calculated the probability of

achieving greater than or equal to the minimally important

difference in the treatment group and used probabilities in both

groups to acquire the risk difference for achieving greater than or

equal to the minimally important difference. Adverse events are

reported as binary outcomes. Associations between treatment and

adverse events are reported as relative risks (RRs) and risk

differences, and were determined using random-effects modeling and

the DerSimonian-Laird method. Stata statistical software version

13.1 (StataCorp) was used. Comparisons were 2-tailed using a P ≤ .05

thresholds. They conducted subgroup analyses if there were 2 or

more studies in a given subgroup and conducted tests of interaction

to establish whether the subgroups differed significantly from one

another. The study also assessed the credibility of significant

subgroup effects (P < .05) using previously suggested criteria. Meta-

regression was performed for length of follow-up, opioid dose, and loss to follow-up.

Results:

96 RCT resulting in 26 169 patients were included. Of the included studies, there were

25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain

present in the absence of tissue damage), and 6 trials of mixed types of pain.
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Santos, Kirsten Gail

In pain relief, opioids were associated with pain relief compared with placebo (weighted

mean difference, -0.79 cm [95% CI, -0.90 to -0.68 cm] on a 10-cm VAS for pain, P < .001).

High-quality evidence from 42 RCTs found that opioids were associated with reduced pain

versus placebo (weighted mean difference, -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm

VAS for pain, P < .001).

In physical functioning, High-quality evidence showed opioids were associated with a

small improvement in physical functioning compared with placebo, but did not meet the criterion

for the minimally important difference (weighted mean difference, 2.04 points [95% CI, 1.41-

2.68 points] on the 100-point SF-36 physical component score, P < .001).

In High-quality evidence, opioids had no association with emotional functioning

(weighted mean difference, -0.44 points [95% CI, -1.09 to 0.20 points] on the 100-point SF-36

mental component score, P = .53), role functioning (weighted mean difference, 0.87 points [95%

CI, -0.54 to 2.28 points] on the 100-point SF-36 subscale for role limitations due to physical

problems, P = .23) compared with placebo.

High-quality evidence showed an association of opioids with improved social

functioning compared with placebo but did not meet the minimally important difference criterion

(weighted mean difference, 1.58 points [95% CI, 0.45-2.70 points] on the 100-point SF-36

subscale for social functioning, P = .006)

High-quality evidence with follow-up lasting 3 months or longer found that opioids were

associated with a small improvement in sleep quality compared with placebo but did not meet

the criterion for the minimally important difference (weighted mean difference, 3.42 mm [95%

CI, 1.58-5.26 mm] on the SF-36 sleep quality 100-mm VAS, P < .001).
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Santos, Kirsten Gail

Opioids were associated with an increased incidence of vomiting; however, this

association was less in the 18 enrichment RCTs (5961 patients) compared with placebo (RR,

2.50 [95% CI, 1.89-3.30], P < .001)

Moderate-quality evidence from 9 RCTs (1431 patients) showed no difference in the

association of opioids versus non-steroidal anti-inflammatory drugs for pain relief (weighted

mean difference, -0.60 cm [95% CI, -1.54 to 0.34 cm] on the 10-cm VAS for pain, P = .21).

Moderate-quality evidence from 7 RCTs (1311 patients) suggested no difference in physical

functioning between opioids and non-steroidal anti-inflammatory drugs (weighted mean

difference,-0.90points [95% CI,-2.69 to 0.89 points] on the 100-point SF-36 physical component

score, P = .33). High-quality evidence from 5 RCTs (2632 patients) showed an association of

opioids with vomiting compared with non-steroidal anti-inflammatory drugs (RR, 4.71 [95% CI,

2.92 to 7.60], P < .001; risk difference, 6.3% [95% CI, 3.2% to 11.1%]).

Conclusion:

In this meta-analysis, evidence from high-quality studies showed that the use of opioid

was associated with statistically significant but small improvements in pain and physical

functioning, and increased risk of vomiting compared with placebo. Opioids compared with non-

steroidal anti-inflammatory medications suggested that the benefit for pain and functioning may

not be significantly different, although the evidence was from studies of only low to moderate

quality.

Relevance to Physical Therapy:

Assignment
Santos, Kirsten Gail

Not only in the United States, but in every country, chronic pain is one of the many

problems that people complain about and one of the major reasons they visit for treatment.

Sadly, most of them would just visit their doctor and get prescribed with pain medications being

not aware that physical therapy can help them. As a result many are reported of dependence on

these medications, and one of them is opioids. And the sad truth sometimes is that some of our

clinicians are abusing the prescription of opioids to patients. Yes, these medicines can help

manage their pain, however long term use and being dependent with it is a different issue that we

as clinicians should be aware of and act on. As this study concluded, we as physical therapists

must highly encourage that pain management can not be addressed with prescription of pain

medication, particularly opioids alone, but instead let us educate people that physical therapy can

majorly help improve their condition. True that drugs can help them, but incorporating physical

therapy will have greater impact. And the most important thing that we should address in this

matter, is that we eliminate the adverse effects of opioids long term use, such as adverse events,

addiction and overdose to name a few. Let us educate people that physical therapy and good

exercise management can help them reduce their pain, improve physical and mental functioning,

and improve their overall well-being.

Assignment
Santos, Kirsten Gail

Wang Z, Shi L, Xu S, Zhang J. Cerebrolysin for Functional Recovery in Patients with

acute Ischemic Stroke: A Meta-analysis of Randomized Controlled Trials. Drug Design,

Development and Therapy. 2017; 11: 1273-1282. Doi:10.2147/DDT.S124273

Purpose:

Many studies have shown that cerebrolysin help acute ischemic stroke patients in the

reduction of infarction volume and improve functional recovery, excitotoxicity defense, decrease

neuroinflammation and apoptosis, promotion of neural sprouting, improving cellular survival and

neurogenesis stimulation. These promising outcomes and efficacy inspired many clinical studies

of cerebrolysin. This research article aims to systematically review several RCTs that evaluate

the effects and discover influencing factors of cerebrolysin in acute ischemic stroke (AIS)

patients on their neurological functional recovery.

Experimental Methods:

In this systematic review and meta-analysis, RCTs were drafted using the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses format guidelines. All RCTs were
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Santos, Kirsten Gail

evaluated by the two authors and should be qualified with the eligibility criteria set: the

following studies should have (1) adult subjects, (2) include 3 months followup after treatment,

(3) patients received intravenous cerebrolysin and (4) outcome should primary include functional

recovery. Secondary outcomes may include mortality, adverse events and serious adverse events.

Risk of bias of all studies was assessed and evaluated with Cochrane Collaboration’s

risk-of-bias tool. All data analyses were performed using Review Manager 5.2 software.

Results:

Six RCTs were identified in the study and a total of 1,649 patients with AIS were pooled

from the six RCTs. In the neurologic outcome scales analysis, cerebrolysin has found no

significant effect on functional recovery to AIS patients at Day 90 in comparison with placebo in

mRS (RR 1.33, 95% CI 0.79-2.24, P=0.28), NIHSS (RR 1.03, 95% CI 0.83-1.28, P=0.77) or BI

response (RR 0.95, 95% CI 0.84-1.08, P=0.44). In the safety analysis, cerebrolysin did not

increase the risk of adverse events (RR 0.98, 95% CI 0.88-1.09, P=0.67), serious adverse events

risk (RR 1.20, 95% CI 0.86, 95% CI 0.86-1.66, P=0.29) or the mortality rate (RR 0.86, 95% CI

0.57-1.31, P=0.49). However, studies noted a large advantage of cerebrolysin in patients with

severe AIS.

Treatment with cerebrolysin was still questionable based on evidence. Cerebrolysin

showed no advantage in global neurological recovery as assessed using mRS, NIHSS and BI.

However, cerebrolysin showed superior results in patients with severe AIS. Cerebrolysin did not

increase the incidence of adverse events, serious adverse events or mortality. Previous outcomes

from neuroprotective therapy have indicated that early intervention a few hours after AIS might

achieve favourable results. Therapeutic window time ranged from 6 hours to 7 days after onset of
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Santos, Kirsten Gail

stroke. Cerebrolysin positive effect was maintained until Day 30 but diminished at 90 days

follow-up. However, the present meta-analysis could not test the neuroprotective effects of

cerebrolysin due to limited data.

Conclusion:

This systematic review and meta-analysis has shown that cerebrolysin has no significant

efficacy on the neurological functional recovery in AIS patients. Cerebrolysin administration to

AIS patients cannot be supported by the RCTs presented in the study and suggested further

studies should focus on the effects of cerebrolysin that is administered within 6 hours after onset

of AIS and patients with severe symptoms.

Relevance to Physical Therapy:

Back in my practice here in the Philippines, year 2017-2018, our head rehabilitation

doctor introduced this medication to our clinic. We have started to treat ischemic stroke patients

who are under cerebrolysin. That’s when I started to get interested in this topic. Because many of

our patients are also asking about this intravenous medicine, it is very costly and they wanted to

know if it could really benefit them and if the results would be very promising. As a physical

therapist, it is our role to provide proper education to our patients and research reviews related to

the drug and therapy. It is one way of assurance that we practice based on evidence and we are

one with them to achieve their goals in recovery.

Based on this systematic review, a favourable outcome of cerebrolysin is evident during

early intervention. Neuroprotective therapy adjunct with physical therapy will have an

achievable result showing accelerated recovery. Therefore, the importance of early intervention a
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Santos, Kirsten Gail

few hours after onset of AIS is very critical. In physical therapy practice, taking advantage of the

therapeutic time window (6 hours to 7 days after stroke onset) might achieve a favorable

outcome and faster recovery for our patients. And more importantly, let us really not forget to

educate our patients the importance of physical therapy to their recovery, this medicine may help

their neural recovery but still exercise and physical therapy should not be neglected.