Relative bioavailability of diclofenac potassium from softgel capsule vs. powder for oral solution and immediate-release formulation

Diclofenac potassium is a type of NSAID that is used to treat mild to moderate pain.  The people who take this medication want it to act as fast as possible, so their pain will subside.  This study has determined which formulation, soft gel, powder for oral solution, or tablet, would provide the fastest results.

The softgel is a newer formulation, combining the benefits of a tablet form and an oral solution.  It gives the medication as a solution in a solid dosage form.  The investigators wanted to see if this would effectively treat pain as quickly as the other two formations.

The patients were given one of the three dosage forms in a 50 mg strength.  They fasted for 10 hours before receiving the dose as well as for 4 hours after receiving the dose. Each subject had to give 17 blood samples over the course of 24 hours.

The study came to a few conclusions.  They determined that taking the oral solution formulation led to the highest mean peak plasma concentrations of the drug.  The amount of time that it took for the softgel formulation to reach its maximum effect was 0.5 hours, which was right between the oral solution (0.25 hours) and the tablet (0.75 hours).  Overall, the study concluded that the effectiveness of the softgel formulation of diclofenac potassium was comparable to that of the oral solution and tablet.  Patient compliance was increased when they had the opportunity to take the softgel.

 

Link to article

Bende, G., Biswal, S., Bhad, P., Chen, Y., Salunke, A., Winter, S., Wagner, R. and Sunkara, G. Relative bioavailability of diclofenac potassium from softgel capsule versus powder for oral solution and immediate-release tablet formulation. Clinical Pharmacology in Drug Development, 2016; 5: 76–82.

NSAIDs Are Associated with Lower Depression Scores in Patients with Osteoarthritis

This study looked at whether or not NSAIDs, as an addition to antidepressant therapy, could decrease depressive symptoms in patients with osteoarthritis.  The study was a multicenter, double-blind, placebo-controlled study with patients who have active osteoarthritis.  Each participant was put into one of three groups: placebo group, ibuprofen 800 mg (three times a day) or naproxen 500 mg (two times a day) group, or Celebrex 200 mg (one time a day) group.  The patients were tested for major depression using the standard health questionnaire-9 (PHQ-9) scale.  Each person was tested at baseline, after two weeks of treatment and after six weeks of treatment.

The results showed that all three groups had similar average PHQ-9 scores at the baseline screening and at the last screening, after six weeks of treatment.  However, there was a detectable difference in change of PHQ-9 score between the groups with the ibuprofen/naproxen group and the Celebrex group having lower scores of .31 and .61 respectively.

The study concludes that NSAID usage in patients with osteoarthritis shows a trend of reduction in depressive symptoms.  I, however, do not believe there was enough evidence in the trial to conclude this.  Additionally, I believe they mistook correlation with causation.  Each group, in addition to a decrease in depression, also saw a decrease in pain.  As we have learned in class, pain can cause depression.  So while NSAID usage may correlate with decreased depression, it may have to do with the pain relief and not the specific mechanism of action of NSAIDs.  To disprove this, NSAIDs should also be compared to other pain relievers with different mechanisms of action.

Rupa IL, Gandhi s, Aneja A, et al. NSAIDs Are Associated with Lower Depression Scores in Patients with Osteoarthritis. Am J Med. 2013;126(11).

http://www.amjmed.com/article/S0002-9343(13)00358-6/abstract

Evolving Therapeutic Strategies to Improve Nonsteroidal Anti-inflammatory Drug Safety

The question of how to treat chronic pain is one that seems to be drawing more and more attention. As people are living longer, more will eventually come to face chronic pain caused by osteoarthritis, diabetes neuropathy, or other chronic conditions. Additionally, increasing misuse of opioid pain medications and the dangerous side effects associated with medications like NSAIDs has pressed for development of alternative forms of pain management. This retrospective analysis of 2177 patient charts looked at the comparative effectiveness of three topical options for chronic pain management: two compounded creams and one NSAID based gel.

Cream I creams contained 20% Flurbiprofen, 5% Tramadol, 0.2% Clonidine, 4% Cyclobenzaprine, and 3% Bupivacaine. Cream II contained 20% Flurbiprofen, 2% Baclofen, 0.2% Clonidine, 10% Gabapentin, and 5% Lidocaine. The NSAID based gel, Voltaren, contains 1% diclofenac sodium. 1141 patients were given Cream I, 527 received Cream II, and 509 patients received Voltaren gel.  Voltaren gel caused a decrease in pain intensity score of 19%, which is statistically significant to be less than the pain intensity decrease caused by both Cream I (37% ) and Cream II (35%). It is hypothesized in the journal article that this increase in efficacy of the two compounded creams stems from the inclusion of multiple active ingredients with different mechanisms of action.

Use of a cream for chronic pain treatment is beneficial in many areas. It can be topically administered at the site of the pain and will have lower systemic bioavailability.  This will lead to less of the dose-limiting adverse effects commonly seen with oral medications such as NSAIDs and opioids. Do you think topical pain medication should always be an option for patients with chronic pain? Can you think of an example of when it may not be as effective as an oral medication?

 

Somberg JC, Molnar J. Retrospective Evaluation on the Analgesic Activities of 2 Compounded Topical Creams and Voltaren Gel in Chronic Noncancer Pain. Am J Ther. 2015;22:342-349.

http://ovidsp.tx.ovid.com/sp-3.18.0b/ovidweb.cgi?&S=BLBGFPDBADDDKCBDNCJKKDDCAJPEAA00&Link+Set=S.sh.13512_1456860318_56.13512_1456860318_68.13512_1456860318_76.13512_1456860318_78.13512_1456860318_82.13512_1456860318_106%7c3%7csl_10

Selective COX-2 inhibitors significantly reduce the occurrence of heterotopic ossification after hip arthroscopic surgery

A well known complication after hip arthroscopic surgery is heterotopic ossification (HO), the presence of bone in soft tissue. This complication can be as prevalent as 44% of patients when no prophylactic intervention is given. Although it is not totally understood how HO occurs, it is known that mesenchymal cells provide the origin for this, and they are activated by inflammatory mediated response in injured tissues. Low-dose irradiation and nonsteroidal anti-inflammatory drugs are the two most commonly used interventions for this problem of reducing and preventing HO. This study hypothesized that postoperative HO prophylaxis using 600 mg of etodolac once daily for two weeks would significantly reduce risk of HO in patients after surgery in comparison with a groups of patients who were treated by the same surgeon who did not receive NSAID prophylaxis. Their ultimate goal of the study was to evaluate the effectiveness of short-term selective COX-2 inhibitors (specific NSAID) when they are being used prophylactically for HO.

In this retrospective analysis of data gathered from a cohort of patients who underwent surgery by the same surgeon for the same reason, femoroacetabular impingement.  Although the study started out with 263 patients patients, 163 were included in the final analysis because 100 of them had to be excluded for various reasons including lost to follow-up, previous hip surgery or HO, and not meeting inclusion criteria. 100 patients were assigned to the control group and 63 were included in the group that received COX-2 inhibitor prophylaxis. In the control group, 35 of 100 patients developed HO. The patients were tested for HO 2 weeks, 6 months, and 1 year after surgery. The data did exhibit a significant difference between the control and study groups, as there were no patients in the study group who developed HO. This is the first study to ever look at a dose this low, half of the maximum, in attempting to prevent HO with this specific medication. It is significant that this research is able to show a short-term, selective NSAID can be used to effectively prevent HO in this patient population because it gives the patients much less of a risk of developing the GI side effects that are so closely associated with traditional NSAIDs.

It is interesting how choosing between medications in the same class can often be very significant when treating a patient and trying to keep them as healthy and happy as possible. In what other classes of drugs can this be significant?
Rath E, Warschawski Y, Maman E, et al. Selective COX-2 inhibitors significantly reduce the occurrence of heterotopic ossification after hip arthroscopic surgery. Sports Med. 2016;44:677-81.

Keeping the Kidneys Safe: The Pharmacists’ Role in NSAID Avoidance

While non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen are very easy to purchase (in grocery stores and gas stations), they are one of the most common medications improperly prescribed, especially to older adults. If these are used at a high dose regularly and combined with the wrong medications, it can lead to acute kidney injury (AKI). NSAIDs inhibit the cyclooxygenase enzyme, preventing prostaglandin production. Prostaglandins help to autoregulate the dilation of arterioles in the kidney, controlling the amount of blood filtered. If AKI goes untreated long enough, self-prescribing NSAIDs can even lead to chronic kidney disease (CKD). Luckily, there are strategies that pharmacists can use to prevent patients from overusing NSAIDs at home and prevent these adverse effects.

Pharmacists can use bright stickers or post-it notes on the prescriptions of those who need medication counseling due to a high risk for AKI or CKD (patients with hypertension or diabetes). This will help the staff to remember to discuss the patient’s personal pain management system during consultations, blood pressure screenings, or when handing out the prescription. If the patient is in a rush, a handout could also be placed in with the prescription or on a pamphlet table so that the information is still available. They can also help to counsel on when to use ice or heat on a musculoskeletal issue, rather than taking an NSAID to relieve pain. This gives the patient other ways to manage their pain without taking an NSAID too frequently.

Acetaminophen could also be recommended as a pain reliever for those who are at high risk for AKI or CKD, as it is metabolized in the liver more than the kidney and is rarely seen to damage the kidney. However, this will then require that the pharmacist counsel on the maximum daily dose for acetaminophen in combination with other acetaminophen-containing medications the patient may have. This would be an optimal alternative if the patient is insistent on taking a pill for their pain, as long as the proper counseling regarding acetaminophen can be delivered.


I felt that this article had a lot of good options for educating patients with increased risk for kidney injuries against NSAID use. The repetition of seeing a helpful handout with the patient’s prescription would demonstrate the importance of the issue. The handout could serve as an additional reminder each time the patient has their prescription filled to steer clear of NSAIDs and use another pain-relieving method. This article also ties in nicely with what we are currently learning in anatomy and physiology and helped my understanding of kidney damage via non-steroidal anti-inflammatory drugs.

http://www.japha.org/article/S1544-3191(15)30021-2/fulltext

Pai, Amy B. “Keeping kidneys safe: The pharmacists’ role in NSAID avoidance in high-risk patients.” Journal of the American Pharmacists Association. 55.1 (2015) e15-e25. Web. 14 February 2016.

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion

Pleural effusion is a condition in which fluid collects between tissues lining the lung and chest.  This condition can be painful and may lead to infection.  It can often be treated with antibiotics or diuretics, but sometimes it is necessary to physically deplete the space between the tissue via a surgical procedure known as pleurodesis.  This randomized clinical trial compared the efficacy of pain treatment for the procedure between opioids, which are the current go-to treatment, and NSAIDs.

NSAIDs had previously been avoided for this type of procedure due to fear that they might decreases the efficacy of pleurodesis; however, this study found that not only did the NSAIDs result in similar pain scores, but they also resulted in noninferior pleurodesis efficacy.  These results demonstrate that NSAIDs are essentially equivalent to opioids in effective pain management following pleurodesis, while also not negatively affecting the efficacy of pleurodesis itself.

These results offer an interesting and favorable pain management option. The growing incidence rates of opioid abuse and opioid-related death have led health professionals to look for other viable pain management options when possible.  Recently, an emergency department in New York successfully attempted to run a whole shift without giving opioids to patients (http://www.ashpintersections.org/2016/02/pharm-d-m-d-team-successfully-enacts-opioid-free-ed-shift/).

Personally, I am excited to see the results of this clinical trial.  I believe we will need to begin looking for other viable methods of pain management following surgery or injury to combat the growing opioid epidemic in the US.  Hospitals can begin to use this kind of data to try prescribing alternative medications such as NSAIDs when safe.  Although NSAIDs come with their own set of problems and are especially unsafe in older patients, there are many cases in which it could be a superior option to opioids.

Do you think it is feasible to significantly reduce prescription and usage of opioids for pain management, or do you believe will it be near impossible to make this transition in the near future?

Rahman NM, Pepperell J, Rehal S, et al. Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial. JAMA. 2015;314:2641-2653.

http://jama.jamanetwork.com/article.aspx?articleid=2478201