In some patients, interferon-beta therapy is associated with specific adverse events, such as injection-site reactions and flu-like symptoms.1–7 Evidence indicates that these adverse events
occur with a higher frequency at the beginning of interferon-beta therapy and tend to decrease over time.1,2,11Injection-site
reactions are of particular concern to the clinician because they may ultimately affect treatment acceptance and, hence, compliance.
Anecdotal clinical data suggest that interferon beta-1a may be associated with greater injection-site pain and injection-site reactions than interferon beta-1b. A phase 1 study in 64 healthy volunteers concluded that injection-site pain was three times higher with interferon beta-1a (43%) than with interferon beta-1b (14%, P < .0001).12The mean severity of
pain at 30 minutes postinjection, assessed with a 10-cm visual analog scale (VAS) score, was also significantly lower with interferon beta-1b (0.01 cm) than with interferon beta-1a (0.11 cm, P < .0001). These findings are supported by evi-dence from a blinded assessment of injection-site reactions showing that 71% of injections with interferon beta-1b were free from local reactions versus only 47% among patients receiving interferon beta-1a (P < .0001).12
To date, studies have measured injection-site pain and reactions in healthy volunteers. The current exploratory pilot The authors are affiliated with the University of Calgary MS Clinic,
Foothills Medical Centre, Calgary, Alberta, Canada.
W
ell-controlled studies have shown that interferon beta-1b (Betaseron) is a safe and effective disease-modifying therapy for patients with relapsing-remitting (RR) and secondary progressive (SP) multiple scle-rosis (MS).1–4Since its approval for RRMS in 1993, interferonbeta-1b has become widely prescribed around the world. Two other interferon-beta preparations have since been licensed for the treatment of RRMS: subcutaneous and intramuscular preparations of interferon beta-1a, marketed as Rebif and Avonex, respectively.5–7
Recent evidence suggests that treatment of MS with high-dose, high-frequency subcutaneous administration of interfer-on beta is more effective than interfer-once-weekly intramuscular administration.8–10 Two high-dose, high-frequency
interferon-beta therapies are available: subcutaneous interferon interferon-beta-1b 250 μg every other day and subcutaneous interferon beta-1a 44 μg three times weekly. Although the clinical efficacy and tolerability data from the original pivotal trial studies of these treatments appear to be similar,1–6 direct comparative data
between the treatments are not yet available.
Injection-Site Pain in Patients With
Multiple Sclerosis: Interferon Beta-1b
Versus Interferon Beta-1a
Colleen Harris, RN, MN, NP; Kathy Billisberger, RN; Lori Tillotson, RN, BN; Sharon Peters, RN, BN;
Carol Pederson, RN, BN; Melodie Becker, RN, BN
A single-center, open-label, comparative pilot study was undertaken to assess injection-site pain
associ-ated with 10 consecutive subcutaneous injections of interferon beta-1b 250 μg every other day or
interferon beta-1a 44 μg three times weekly in patients with multiple sclerosis (MS). Injection-site
pain was assessed by the patients with a 10-cm visual analog scale (VAS) score. Recordings were made
before each injection and at 10 minutes, 1 hour, and 24 hours postinjection. Ten patients were
enrolled in each treatment group. The proportion of injections associated with no pain or no increase
in pain at 1 hour postinjection was higher with interferon 1b (47%) than with interferon
1a (27%). Mean pain severity was also less intense with interferon 1b than with interferon
beta-1a. Differences in VAS scores were seen immediately after injection (1.04 versus 3.14 cm, respectively)
and at 10 minutes (0.40 versus 1.70 cm) and 1 hour (0.33 versus 1.50 cm) postinjection. These
find-ings indicate that subcutaneous injection with interferon beta-1b is associated with a lower incidence
and severity of pain than subcutaneous injection with interferon beta-1a in patients with MS. The
results should assist MS nurses and physicians in supporting patients to make an informed choice
regarding potential side effects when deciding on an appropriate disease-modifying therapy.
Int J MS
Care. 2005/2006;7:132–136.
study (Canadian Betaseron Versus Rebif Study on Injection-Site Pain [CRISP]) was designed to assess the incidence and severity of injection-site pain associated with subcutaneous administration of the two high-dose, high-frequency interfer-on-beta treatments in patients with MS. The data and obser-vations derived from this study will be used as the basis for development of a larger trial that should determine whether any difference that exists between the two treatments is clini-cally or statisticlini-cally significant.
Patients and Methods
This phase 4, single-center, open-label comparative pilot study included patients 18 years of age or older who were receiving subcutaneous interferon beta-1b (250 μg [8 MIU]) every other day or interferon beta-1a (22 μg [6 MIU] or 44 μg [12 MIU]) three times weekly. The patients had all been receiving their prescribed interferon beta for at least 1 month but not more than 6 months before entering the study. Inter-feron beta-1b was provided as lyophilized powder and inter-feron beta-1a as prefilled syringes or lyophilized powder. All patients used an autoinjector to administer their medication, with each patient using the same autoinjector throughout the study. A trained nurse gave all patients instruction on how to inject their medication, and all injections were self-administered.
Patients with exacerbations of MS within 1 month before study entry were excluded, as were patients considered at risk of noncompliance or otherwise unsuitable for study participa-tion (eg, patients with cognitive or psychosocial issues that would make self-injection difficult). None of the patients par-ticipated in an investigational clinical trial within 1 month of
study entry or at any time during the course of this study. No patient had depressive symptoms before the study. All patients at the University of Calgary MS Clinic, Alberta, Canada, who met these criteria were offered the opportunity to participate in the study. All patients gave written informed consent before undergoing any study-related procedures.
Pain associated with the first 10 consecutive injections of interferon beta-1b and interferon beta-1a was recorded by the patients in VAS score diaries. The 10-cm VAS scale used ranged from “no pain” (0) to “worst possible pain” (10). Assessments were made immediately before and after each injection and 10 minutes, 1 hour, and 24 hours postinjection over 3 weeks. The primary endpoint was the mean change in VAS score from baseline (preinjection) to 1 hour postinjec-tion. Secondary endpoints were the mean changes in VAS score from baseline to immediately after injection, 10 minutes postinjection, and 24 hours postinjection.
Descriptive statistics were used to summarize the enroll-ment data and efficacy endpoints in both treatenroll-ment arms at each scheduled time point.
Results
Ten patients were enrolled in each of the two treatment groups. As shown in Table 1, the groups were well matched with respect to demographic and disease characteristics. Patients used similar sites for injection, the most common being the abdomen, buttock, and thigh.
In total, 47 of the 100 injections (10 consecutive injec-tions in each of 10 patients) of interferon beta-1b were pain free, compared to only 27 of the 100 interferon beta-1a injec-tions. The primary efficacy endpoint, pain score at 1 hour Table 1. Patient and disease characteristics
Characteristic Interferon beta-1b (n = 10) Interferon beta-1a (n = 10)
Age, y (mean ± SD) 37.5 ± 11.2 34.7 ± 7.2
Sex, n
Male 2 1
Female 8 9
Type of multiple sclerosis, n
Relapsing remitting 8 10
Secondary progressive 2 0
Kurtzke Expanded Disability Status Scale score* (mean ± SD) 3.4 ± 1.3 2.6 ± 0.8
Mean duration of interferon-beta therapy before study, mo 2.9 3.4
No. of injections in area†
Abdomen 33 29
Buttock 30 25
Thigh 34 38
Other 3 8
*A method of quantifying disability in multiple sclerosis. †Total of 100 injections given.
0.6 0.33 0.4 1.04 0.32 1.5 1.7 3.14 0 1 2 3 4 5 6 Immediately 10 min 1 h 24 h Time postinjection
Mean change in VAS score
from baseline (cm)
Interferon beta-1b Interferon beta-1a postinjection, was markedly lower with interferon beta-1b. Figure 1 compares the mean change from baseline across all 100 injections in each group at each time point that assess-ments were made. These data clearly show that interferon beta-1a was associated with a greater mean increase in pain score than interferon beta-1b immediately after injection and 10 minutes and 1 hour postinjection. Scores at 24 hours were similar in the two groups. Subcutaneous injections of interfer-on 1b were cinterfer-onsistently less painful than interferinterfer-on beta-1a injections after 1 hour across the whole series of 10 injec-tions (Figure 2). The same consistent advantage of interferon beta-1b was observed immediately after injection (data not shown) and at 10 minutes postinjection (Figure 3). No differ-ences in injection-site pain were observed between treatments at 24 hours postinjection.
Discussion
Chronic pain is a significant problem for patients with MS, with as many as 44% of patients stating that “persistent bothersome pain” reduced their quality of life.13–16
Additional-ly, patients reporting chronic pain were also significantly more likely to report depressive symptoms than those without.16,17
The prevalence of chronic pain in patients with MS under-scores the importance of addressing pain and minimizing any factors that cause additional pain. Reducing the pain associat-ed with injection of any treatment also has important implica-tions for improved treatment adherence. Evidence suggests that high-frequency administration of high-dose interferon beta-1b and interferon beta-1a are effective in treating MS and have similar efficacy.1–6
Although mostly mild, and declining in frequency with increased time on therapy, injection-site reactions to the inter-feron betas are common in clinical trials and in everyday prac-tice.1,2,4,11,18,19After 1 year of treatment, however, the
propor-tion of patients experiencing such adverse events is reduced.
Figure 1.Mean change from baseline in visual analog scale (VAS) score after administration of 10 consecutive doses of interferon beta-1b or interferon beta-1a in 10 patients with multiple sclerosis. Error bars are standard deviations.
Furthermore, these reactions can be managed with simple techniques such as rotation of injection sites, use of autoinjec-tors, and concomitant use of antihistamines or nonsteroidal anti-inflammatory drugs.20
The main problem with the traditional injection method may lie in the use of the same needle to reconstitute and administer the drug, resulting in the presence of active drug on the exterior of the needle, which then comes into contact with the skin when the injection is given. Self-injection may also result in inconsistencies in injection depth and adminis-tration rate, which may increase the likelihood of pain and irritation. The automated injection system adopted in our study used interferon-free needles and ensured that medica-tion was delivered at a consistent rate, delivery angle, and depth of penetration, thereby improving the consistency of the injection process for both interferon-beta products tested in our trial. A recent phase 4 open-label study found that the use of an autoinjector to administer interferon beta-1b (250 μg) every other day for 21 days in patients with MS Figure 2.Mean change from baseline in visual analog scale (VAS) score at 1 hour after administration of each of 10 consecutive doses of interferon beta-1b and interferon beta-1a in patients with multiple scle-rosis. Error bars are standard deviations.
0 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 Injection number
Mean change in VAS score from
baseline at 1 hour postinjection (cm)
Interferon beta-1b Interferon beta-1a
Figure 3.Mean change from baseline in visual analog scale (VAS) score at 10 minutes after administration of each of 10 consecutive doses interferon beta-1b and interferon beta-1a in patients with multi-ple sclerosis. Error bars are standard deviations.
0 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 Injection number
Mean change in VAS score from
baseline at 10 min postinjection (cm)
Interferon beta-1b Interferon beta-1a
4. European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet.
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5. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised dou-ble-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):
1498–1504.
6. Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interfer-on-beta1a in relapsing-remitting multiple sclerosis: Prevention of Relaps-es and Disability by Interferon-Beta1a Subcutaneously in Multiple Scle-rosis. Ann Neurol. 1999;46(2):197–206.
7. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis: the Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol.
1996;39(3):285–294.
8. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet.
2002;359(9316):1453–1460.
9. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology. 2002;59(10):1496–1506.
10. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technolo-gy Assessment Subcommittee of the American Academy of NeuroloTechnolo-gy and the MS Council for Clinical Practice Guidelines. Neurology.
2002;58(2):169–178.
11. Gaines AR, Varricchio F. Interferon beta-1b injection-site reactions and necroses. Mult Scler. 1998;4(2):70–73.
12. Baum K, Hunter S, Gariepy S, Potrin D, Morelli G. COMFORT (COM-parative study FOR Two high-dose interferon-1bs): evaluating tolerabili-ty of high-dose, high-frequency interferon-b treatment [abstract]. Mult Scler. 2004;10(suppl 2):S239.
13. Archibald CJ, McGrath PJ, Ritvo PG, et al. Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients. Pain.
1994;58(1):89–93.
14. Kassirer M. Multiple sclerosis and pain. Int J MS Care. 2000;
2:30–38.
15. Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis.
Neurology. 1988;38(12):1830–1834.
16. Ehde DM, Gibbons LE, Chwastiak L, Bombardier CH, Sullivan MD, Kraft GH. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler. 2003;9(6):605–611.
17. Williams LS, Jones WJ, Shen J, Robinson RL, Weinberger M, Kroenke K. Prevalence and impact of depression and pain in neurology outpa-tients. J Neurol Neurosurg Psychiatry. 2003;74(11):1587–1589.
18. Kappos L, Polman C, Pozzilli C, Thompson A, Beckmann K, Dahlke F. Final analysis of the European multicenter trial on IFNbeta-1b in sec-ondary-progressive MS. Neurology. 2001;57(11):1969–1975.
19. Elgart GW, Sheremata W, Ahn YS. Cutaneous reactions to recombi-nant human interferon beta-1b: the clinical and histologic spectrum. J Am Acad Dermatol. 1997;37(4):553–558.
20. Bayas A, Rieckmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Saf. 2000;22(2):149–159.
21. Tornatore C, Bar tlett D. Tolerability of inter feron beta-1b (Betaferon/Betaseron) can be significantly improved using both inter-feron-free needle and automated infection techniques. J Neurol.
2002;249(suppl 1):I/205.
resulted in a 58% reduction in the incidence of injection-site pain compared with the conventional injection method.21
Another method used to help prevent injection-site reactions is rotation of injection sites, and gluteal sites appear to best tolerate the injections (K. Baum, unpublished data, 2005). Also, manufacturers recommend that the injection solution be at room temperature before administration.22,23
Subcutaneous administration of interferon beta-1a has been postulated to be associated with more pain than interfer-on beta-1b either because its formulatiinterfer-on is more acidic or because of differences in drug concentration or structure. Dif-ferences in other components of the injected solution (eg, the buffer, cosolvents, chelating agents, antimicrobial preserva-tives, tonicity, and osmolarity) may also play a role.24
The results presented in this pilot study suggest that sub-cutaneous administration of interferon beta-1b is associated with lower incidence and severity of injection-site pain than interferon beta-1a in patients with MS. This difference was seen at all time points measured during the study up to 1 hour. These findings support those of COMFORT (Compar-ative Study for Two High-Dose Interferons) in healthy volun-teers.12 Both studies showed that the incidence of
injection-site pain was approximately 1.5 times higher with interferon beta-1a than interferon beta-1b. In our study in patients with MS, the incidence rates were 73% versus 53%, whereas the incidences were 71% versus 47%, respectively, in healthy vol-unteers. The BRIGHT (Betaseron Versus Rebif Investigating Higher Tolerability) study intends to substantiate these find-ings. The study will test whether the high-dose, high-frequen-cy subcutaneous administration of interferon beta-1b is asso-ciated with a lower incidence and intensity of injection-site pain and reactions than interferon beta-1a in a clinically and statistically robust setting in patients with MS.25Knowledge
of differences in injection-site pain among different interfer-on-beta products is an important aspect of treatment, assist-ing MS nurses and physicians in supportassist-ing patients to make an informed choice regarding potential side effects when deciding on appropriate disease-modifying therapy.
References
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Acknowledgment: This study was supported by a grant from
Berlex Canada.
22. Betaferon [package insert]. Montville, NJ: Berlex; 2002. Available at: http://www.berlex.com/html/products/pi/Betaseron_PI.pdf. Accessed 9 August 2005
23. Rebif medication guide. Rockland, MA: Serono, Inc.; updated Septem-ber 2005. Available at http://www.rebif.com/assets/pdfs/Rebif_ medication_guide.pdf. Accessed 9 August 2005.
24. Brazeau GA, Cooper B, Svetic KA, Smith CL, Gupta P. Current perspectives on pain upon injection of drugs. J Pharm Sci. 1998;
