Can you shoot subutex

The biopsy of this lesion showed refringent material in the perivascular inflammatory infiltrate compatible with non-organic particles figure 1B. Transmission electronic microscopy showed very dense particles compatible with inorganic insoluble particles figure 1C.

Spectral analyses of these particles by energy-dispersive x-ray spectroscopy show the presence of silica figure 1D: magnification of figure 1C inlay. Silica has been observed, in most of the particles suspected. A: necrotic livedo-like dermatitis lesion from the lower left leg. The red arrow represents the injection site.

B: macrophages easily distinguished by CD68 immunolabelling among a perivascular inflammatory infiltrate exhibited few refringent material red arrows.

C: transmission electron microscopy, we have observed non organic very dense particles, without epoxy permeation but with either a round shape compatible with silica or with a laminated aspect compatible with silicate. D: High magnification of figure 1C inlay by transmission electron microscopy and energy-dispersive x-ray spectroscopy spectra analysis. Particles primarily identified as very dense and non organic contain silica Si. The increasing incidence of cutaneous complications due to injected buprenorphine generics prompted us to study in vitro solutions that were self-injected by the patients.

The main goal of this study was to put forward particularities that could explain the cutaneous lesions, by qualitatively and quantitatively confronting Subutex and generics solutions. At the time of this study, all sublingual generic formulation available in France Arrow, Biogaran, Mylan, Sandoz and Teva was produced from the same factory and contained the same qualitative raw material. Six different solutions were obtained.

When 2 tablets were necessary, 2 identical solutions were independently prepared and extemporaneously mixed. Talc and magnesium stearate used as an indicator for the elementary analysis were purchased by the Cooper laboratory Melun, France.

Buprenorphine calibration curve 0, 5, 7. The FSC parameter relative size is a measurement of the amount of the laser beam that passes around the cell. This gives us a relative size for the cells using a known control. We have diverted this technology to determine the relative size of the suspended particles in the various studied solutions.

BD Fluorosphere 4. Size distributions of particles in solution were determined using a laser diffraction granulometer LS Analyser, Beckman Coulter. The size measurement is based on the relationship between the light intensity and particle diameter. The size was calculated in terms of the distribution of volume percentages on the basis of the Fraunhofer approximation with an overall sizing range going from 0.

Each sample was measured 10 fold. The solutions were filtered with Durapore polyvinylidene difluoride, 0. Size, form and composition of particles disposed on the membrane were analyzed.

The compositional particles analysis was determined by energy dispersive system X-ray analysis Inca Oxford instrument, UK. Following the French Health Authorities decision to implement a specific and prospective national case collection of these cutaneous complications, Nantes clinical pharmacology department was named to coordinate the investigations.

Briefly, health professionals practicing in drugs users care center have been aware of these cutaneous problems and encouraged to report cases of unusual complication in bubrenorphine user. Statistical analyses used Graphpad Prism 6. The non-parametric Mann-Whitney test was used to identify differences in granulometry study. The galenic analysis, which compares the 2 formulations, underlines differences in the presence of insoluble excipients, under the dissolution conditions that we used.

Subutex consists of only one magnesium stearate insoluble excipient, whereas 3 insoluble excipients are present in the generic form: magnesium stearate, talcum and colloidal anhydrous silica. In water, corn starch creates a viscous suspension, which cannot be considered as particular. Quantitatively speaking, a generic tablet weighs mg, versus mg for a Subutex tablet. Preparing the solutions according to the protocol used by drug users rapidly appeared to be the critical stage of our study.

Filtrating a solution requires some skill, and it appeared to be a source of important interindividual variability. In order to characterize this variability, we based our study on a quantifiable parameter by systematically dosing the buprenorphine in the solutions produced for the study. Figure 2 represents the absolute quantity of buprenorphine, collected in each of the 6 conditions mentioned in Material and Methods.

For a considered condition, there are no significant statistical differences between the two drugs. The observed differences depend more on filtration conditions than on tested drug. Cotton pad use significantly decreases the quantity of collected buprenorphine, whichever drug is considered. This results can be explained by the important void-volume of cotton pads —measured concentrations are similar to other conditions, but the collected volume is smaller.

One tablet of buprenorphine 8 mg Subutex or generic was diluted in 1 ml of sterile water. Drug concentration was monitored with chromatographic method before filtration or after cotton-filtration or Sterifilt-filtration for the Subutex or its generic. The volume of liquid obtained after filtration was assessed by weight difference between the vacuous syringe and full syringe.

The concentration value was transformed in percentage of the nominal dosage 8 mg. The laser granulometry technology is dedicated to particle size distribution analysis. The bar charts are represented on Figure 3A for Subutex and generics. The NFS and NFG solutions showed a multimodal and polydispersed distribution of particle sizes with respectively a mean diameter of The granulometric profiles of the 2 drug solutions are therefore significantly identical.

The granulometric analysis on the SFS solution could not be performed for lack of a large enough number of particles. A: Laser granulometry analysis. Laser light scattering particle size histogram of particles in solution.

Values are reported for volume-weighted analyses. B: Flow cytometry particles analysis. Size range and number of particles present in solution were evaluated by flow cytometry.

Percentage of particles was indicated in the corresponding gate. Absolute number of particles is indicated in the tables under the corresponding dotplot. For each size range, the percentage of reduction between unfiltered and cotton-filtered or sterifilt-filtered solution was calculated.

Values are reported in probability axis. The analysis of the various solutions by flow cytometry confirms the presence of an important quantity of suspended particles figure 3B. When not filtered, a Subutex solution mainly contains particles which size is over 4. Overall, the absolute number of particles measured is systematically higher in the generic solution than in Subutex figure 3B.

Figure 3C represents how the number of particles shrinks under the various conditions. For Subutex, cotton filters enable to reduce by For the buprenorphine generic, this particle number reduction by cotton filtration was respectively by The same comparison made between non- filtered solutions and Sterifilt use shows a reduction by SEM has been used to visualise the size and shape of particles present in solution.

The main part of corn starch contained in the 2 types of tablets was eliminated diluting each solution in ultrapure water. The goal was to remove the interferences related to corn starch crystallization. Under these conditions, only the insoluble particles from the various solutions got on the filtration membrane. The SEM images of NFG show at least 2 different types of material: the first population was almost uniform in size and shape, whereas the second one was much smaller and much more heterogeneous in terms of shapes, more like fragments.

After cotton filtration, and whatever the drug, particle density strongly decreases compared to the non filtered condition. In the case of Subutex, the particles found are identical to those of NFS, in terms of size and shape. For the generic, several populations that were not retained by the cotton filter could be identified. It also includes the population of very small particles, which cover both the first particle population figure 4G and the free surface of the membrane, therefore virtually hiding all the pores figures 4J dashed line circle.

After a Sterifilt is used, the particles are almost absent whichever drug is considered. C—E and H—J: the magnification of the scanning microscope being varied from to after carbon-coating. Figure 5 shows scanning electron microscopy images and energy-dispersive x-ray spectroscopy spectra for Subutex tablets and CFS and generic tablets and CFG.

The systematic presence of the fluorine peak originates in the very nature of the filtration membrane that is used polyvinylidene difluoride. Analyzing the edge of the tablets tablets sliced in 2 reveals a strong abundance of C and O whereas Mg is only detected with difficulty, whether with Subutex or generic.

The absence of magnesium detection in the insoluble particles in the CFG and CFS conditions is probably due to the small amount of magnesium present in the 2 types of tablets, combined with insufficient sensibility of the technique.

The main difference this analysis reveals is the presence of silica in the majority of CFG insoluble particles, and the absence of it in the CFS condition. The origin of silica talc or colloidal anhydrous silica cannot be precisely determined. However, these results confirm the presence of insoluble particles of different nature in the 2 types of solution.

White frame indicates the particles and areas analyzed. For all spectra, the large peak to the left of the carbon C peak is background noise, and the peak of fluor F is from the membrane filter. Typical spectrum of particles found inside the tablets of Subutex A and inlay and generic C and inlay showing only C, O oxygen and small Na sodium , Mg magnesium and Cl chloride peaks for the 2 drugs plus silica Si only for the generic. The 2 lower spectrums show peaks obtained with pure pharmaceutical magnesium stearate and talcum.

Buprenorphine is one of the non-injectable drugs most diverted by drug users. A self-injecting drug significantly increases the administered doses, and therefore increases felt effects but also the involved risks.

In France, the risk reduction policy associated to drug consumption by injectable route showed its value in the reduction of overdose death prevalence and of infectious diseases HIV, CHV…. The main actions that were taken over the last 30 years were based on reducing the infectious risk, through authorizing over-the-counter syringe sales in pharmacies, and then through providing prevention kits Steribox. Beyond the infectious risk, other worrying problems are associated to insoluble particles injection: phlebitis, pulmonary embolisms, « puffy hand » syndrom … [12] — [17].

In order to prevent these complications from occurring, filtrating the injected solutions has become necessary. After the end of the 90s, different types of filters have been provided for users — sterile cotton filters available in the Steribox and the Sterifilt which were provided in the Reception and Harm Reduction Support Centres for drug users CAARUD , and in other low demand threshold structures or harm reduction structures. The cotton filters are relatively easy to use, but they present 2 major drawbacks: they let through big particles in the solution possibly cotton fibres , and present an important void volume, which causes a substance loss leading to an increased filter misuse selling, sharing, reusing, « squeezing ».

Determining buprenorphine « extractability » had up to now never been studied in real use conditions. The quantity of buprenorphine retained by the cotton filters is superior to that of Sterifilt, translating in fine into an inferior injected doses after cotton-pad filtration , compared to Sterifilt. These results can be compared to those obtained with heroin [18].

The main question we have wanted to answer is the origin of the cutaneous necrotic lesions, mainly livedo-like dermatitis LLD , observed almost exclusively during the injection of the generic [10]. Presently, LLD pathogenesis has not completely been solved. The first cases of Nicolau syndrom occurred after intramuscular injection of bismuth salt for the treatment of syphilis dates back to the twentieth century [19].

Most of cases of LLD have been reported after intramuscular injection of non steroidal anti-inflammatory, antibiotic penicillin, aminoglycosides or glucocorticoids drugs, and more recently by self injection of etanercept [20] — [25]. Three reports of LLDs after buprenorphine injection have been previously reported and confirmed by histological findings [35] — [37]. All cases took place in the context of intra-arterial injection.

Skin biopsies showed extravascular or intravascular foreign bodies associated with inflammatory infiltrates. The features of these foreign bodies were typical of starch particles. Recently, Hornez et al. Potier et al. Schneider et al. These results are consistent with the skin biopsy of the patient depicted in figure 1 : dermatologists identified necrotic lesion, and biopsy reveals thrombosis, perivascular inflammation, non-organic refringent particles and particles containing silica.

The main hypothesis is that a vascular mechanism could be involved. In this physiopathological context, we have oriented our research towards the detection of particles potentially present in the solutions that drug users can self-inject.

Moreover, this cut-off is in accordance with the European Pharmacopeia concerning injectable preparations. Detecting these particles in the various tested solutions is not easy. Indeed, although the different pharmacopeia European, American… precisely describes which controls should be performed on active substances and on certain excipients, these recommended techniques cannot be used in the context of our study.

In aqueous solutions, granulometric studies require important dilution; for this work, the solutions had to be diluted in a final volume of mL. This obligation causes reduced sensibility, which explains the absence of results for the SFS condition figure 3A. That is why we have diverted the flow cytometry from its usual application, in order to study the number of particles and their size range.

Combining these 2 approaches allowed us to apprehend the distribution of insoluble particles. These results are in accordance with the work of Roux et al. The second step of this work was to identify the nature of the particles in solution. Although the infrared spectroscopy and the scanning electronic microscopy are reference techniques, the nature of solutions makes it impossible to exploit the results.

The main obstacle is due to the large amount of corn starch present is both drugs. In aqueous solution, this excipient transforms into a opaque and viscous colloidal solution, called starch dressing, which crystallizes after it has dried and covers the other particles, which makes it hard or even impossible to interpret the analyses.

In order to eliminate corn starch, the solutions were diluted before being filtered on a 0. Under these analytical conditions, the difference in appearance of the insoluble particles retained on the filtration membrane is obvious. This characteristic is present both before and after cotton filtration figure 4.

This difference is even stronger when we take a look at the filtrating membrane pore visibility: they are almost completely blocked by the insoluble particles present in the CFG solutions, whereas they are apparent with the CFS solutions figure 4E versus 4J, dashed line circle. These results confirm the data obtained by flow cytometry and by laser granulometry: the CFG condition presents a larger proportion of particles which size is inferior to 4. The heterogeneity of these particles is also apparent on SEM images of the section surface of an untampered tablet, that is to say, before any « misuse » has occurred.

The SEM data obtained after Sterifilt filtration are not displayed because they are not exploitable given how extremely rare the apparent particles are on the filtration membrane surface. Therefore, after having diluted a buprenorphine tablet, only the Sterifilt seems to be capable of retaining the whole of insoluble particles, even when their size is inferior to the filter sieve.

This discrepancy is probably linked to the detection systems, which use light diffraction laser granulometry and flow cytometry. These techniques cannot establish a distinction between a small particles aggregate and a sole particle. Data four months after the study period were also collected.

Drug misuse measures were recorded as follows: 1 Drug misuse history at the time of entering the clinic; 2 any relevant medical history; 3 signs of buprenorphine misuse before the switch from Subutex to Suboxone and at weeks 1—4 following the switch as evidenced by the presence of fresh needle marks or patients volunteering the information ; 4 signs of misuse of other opioids urine tests and patient reports ; and 5 current misuse of any non-opioid drugs urine tests and patient reports.

Length of non-opioid drug use was also recorded. Adverse events considered being associated with the switch from Subutex to Suboxone on the day of the switch, days 2 and 3, and weeks 1 to 4 following the switch were recorded. Adverse events four months after the study period were also collected. The MedDRA coding was followed. Overall patient complacence patient satisfaction with the switch to Suboxone: yes, no, why not and compliance, with reasons for non-compliance where available , were recorded on each of the weekly visits to the clinic before and after the switch.

The Finish maintenances treatment legislation on the time of this study states that only good patient compliance allows take-home medication, and at the most for 8 days. Thus, the frequency of weekly visits gives an indirect implication of compliance; the less visits the better compliance. The 5 treatment centers were located in different parts of Finland. All study doctors were either psychiatrists or general practitioners with long experience in maintenance treatment, and had subspecialty in addiction medicine.

Primary outcomes were the dose of buprenorphine before and after switch to Suboxone, and physical signs or patient reports of intravenous misuse of buprenorphine. The records from a total of 64 patients were examined for this study. The mean age and other background demographics are shown in Table 1. By the end of the 4-week study period, one patient discontinued the maintenance treatment program and three patients were transferred back to Subutex.

Out of these three patients, one was transferred back to Subutex due to adverse events and the other 2 patient for a lack of compliance on Suboxone. During the four months follow-up period, the treatment was discontinued with seven The main reasons for change of treatment or discontinuation were IV misuse of buprenorphine 10 patients , misuse of other drugs 8 patients , adverse events 6 patients and dissatisfaction with Suboxone 5 patients.

Fifty-eight patients One patient was transferred with a higher Suboxone dose 2 mg , two with lower doses 2—4 mg and three patients were "titrated" with daily increases of Suboxone patient anxiety over the transfer up to the previous Subutex dose Table 2.

Out of the 60 patients finishing the 4-week study period, 53 patients During the 4 week period, 4 patients 6. Two patients 3. Out of the 26 patients continuing treatment with Suboxone, 10 patients At baseline, 9 patients Forty-seven patients Information on IV misuse of buprenorphine was not recorded for 8 patients Twenty patients At weeks one, two and three, seven, three and six patients, respectively, showed signs of IV abuse of buprenorphine Subutex or Suboxone.

Three patients who had records of IV-misuse at baseline did not continue misusing during the 4-week follow up period, and three new patients with IV-misuse were observed during this period. Over the 4-week study period, there was no evidence of misuse of other opioids.

During the follow-up period the total number of incidents of IV opiate abuse remained at the same, 10 patients were recorded as showing signs of intravenous buprenorphine Subutex or Suboxone misuse and 1 patient informed the investigator that he had used heroin.

One patient tested positive for codeine, which was permitted for a known complaint. Of the buprenorphine IV abuse, Suboxone was misused intravenously once each by 4 patients and twice by 1 patient. These 5 patients all reported that injecting Suboxone was like injecting "nothing" with any euphoria or that it was a bad experience. Four of them reported also that while they tried to inject Suboxone, they would not repeat the experience.

The highest rate of compliance occurred at Centre Raahe where all patients used Suboxone treatment throughout the 4-week study period. During the 4-week observation period, approximately half the patients were satisfied with Suboxone treatment. At centre HDL, patient satisfaction was Clinic visits across the centers varied from once per week to five visits per week. The switch from Subutex to Suboxone did not change the frequency of visits, and frequency did not change over the 4-week study period.

Twenty-four patients The 14 other patients Twenty-six of the 27 patients During the four week study period, 32 of the 64 patients Gastrointestinal adverse events were the most commonly reported adverse events. Nausea and gastrointestinal pain were the most common adverse events, being experienced by 13 Other common adverse events were fatigue 8 patients, During the 4-month follow-up period, 16 patients One patient discontinued treatment with Suboxone during the 4-week study period due to adverse events, and 5 patients discontinued due to adverse events during the follow-up period.

There were no deaths or other serious adverse events reported for patients in the study. There was no apparent relationship between the average Suboxone daily dose taken during the 4-week study period and the reporting of adverse events. The study has several limitations. Due to the retrospective nature of the study, there were no control groups and the results are only descriptive.

However, the patient data were used to assess any general trends associated with the switch to Suboxone, which may provide an insight into the best clinical practices for using Suboxone as a replacement for Subutex. A survival analysis of the client characteristics and history regarding the time to drop out could have been interesting.

Given the relatively small sample size and the scope of this study, however, this sample may not have sufficient power to detect any but the strongest patterns. Satisfaction and compliance differed significantly amongst the treatment centers, thus site specific issues might account for findings also. The main aim of this study was to follow the medication dose and adverse events during a transfer from buprenorphine to buprenorphine-naloxone combination.

The possible dose adjustments were decided by the doctors and were based on each individual's weaning, withdrawal symptoms and adverse events. However, only one patient discontinued Suboxone due to adverse events or dissatisfaction, and one patient left the treatment program retention rate of This indicates that the side effects at this point probably might not predict patients' likelihood of staying in treatment.

Indeed, patient records indicate that many of the reported adverse events were interpreted as being the result of anxiety about being forced to switch to Suboxone. However, it is notable that during 4 month follow up period only It should be noted anxiety interpretation is more of a speculation than measured assessment. Interestingly, over half of the patients still on Suboxone during the 4 month follow up asked for a dose reduction of Suboxone.

This may indicate that the adverse events could be related to higher buprenorphine serum levels, because buprenorphine in Suboxone has slightly higher sublingual bioavailability than the buprenorphine in Subutex [ 6 ]. The dose reductions of Suboxone were mainly done during the follow-up period which may indicate that bioavailability of high dose of Suboxone in the long term should be more thoroughly investigated.

It should be noted, however, that the earlier Australian study [ 5 ] had found a need for a dose increase, rather than a decrease, when switching from buprenorphine to the combination medication, that could be related to the "low" 12 mg average dose of Suboxone in that study. During the follow-up period relative high number of patients Most of them were either transferred to methadone The most common reason for methadone transfer generally in Finland is polydrug abuse.

It is possible that psychiatric distress, when patients did not feel confident with the forced transfer from Subutex to Suboxone, may lead to "illegally top-up" with Subutex, that in turn could lead to medication change to methadone.

It is possible also, that because the high illicit use of buprenorphine in Finland [ 5 ], the treating personnel had a mistrust on patients reports of Suboxone adverse events, and instead of chancing back to Subutex patients were changed to methadone. Thus, the "forced" transfer event could be a unique situation in Finland and may not be present elsewhere i.

Switching from Subutex to Suboxone did not increase abuse of other opioids. Based on the retrospective nature and small numbers in the study, no solid conclusions about Suboxone diversion can be done.

However, interestingly during the follow-up period of the 60 opioid dependent patients, only 5 patients attempted to misuse Suboxone.

Furthermore, they reported that while they tried to inject Suboxone, they would not repeat the experience, suggesting that the transfer to Suboxone may also serve as part of an overall strategy to curb misuse of buprenorphine. In conclusion, a transfer from Subutex to Suboxone should be carefully discussed and planned in advance with the patients and after the transfer adverse events should be regularly monitored.