Opiate Treatment Research Articles

Disseminating contingency management: Impacts of staff training and implementation at an opiate treatment program

Guided by a comprehensive implementation model, this study examined training/implementation processes for a tailored contingency management (CM) intervention instituted at a Clinical Trials Network-affiliate opioid treatment program (OTP). Staff-level training outcomes (intervention delivery skill, knowledge, and adoption readiness) were assessed before and after a 16-hour training, and again following a 90-day trial implementation period. Management-level implementation outcomes (intervention cost, feasibility, and sustainability) were assessed at study conclusion in a qualitative interview with OTP management. Intervention effectiveness was also assessed via independent chart review of trial CM implementation vs. a historical control period. Results included: 1) robust, durable increases in delivery skill, knowledge, and adoption readiness among trained staff; 2) positive managerial perspectives of intervention cost, feasibility, and sustainability; and 3) significant clinical impacts on targeted patient indices. Collective results offer support for the study's collaborative intervention design and the applied, skills-based focus of staff training processes. Implications for CM dissemination are discussed.

Duration of opiate exposure as a determinant of arterial stiffness and vascular age in male opiate dependence: a longitudinal study

Despite intriguing initial and associational studies, there remains little research on opiate-related arterial dysfunction and no longitudinal studies. As opiates act potently via P16INK4A/CDKN2A identified on GWAS screens, and as arterial ageing is a surrogate for organismal ageing, this area is of general concern. Thirty-eight male controls compared with 198 opiate-dependent male patients were studied longitudinally using SphygmoCor pulse wave analysis. Healthy male controls and opiate-dependent male patients were studied on 125 and 625 occasions, respectively. The mean (±SEM) chronological age (CA) was 42·32±2·22 for controls and 35·04±0·61 for opiate dependent (P=0·0029). 94·4% and 13·2% smoked tobacco (P<0·0001). Controlling for BMI and CA, there was a significant time: addictive status interaction for vascular age (P=0·0127) and central augmentation pressure and index (both P<0·02). Central systolic and diastolic pressures were also worse over time by addictive status (P<0·005). At repeated measures multiple regression adjusted for classical risk factors, opiate dose and duration of opiate use remained significant. The dose-duration effect was significant in 8 terms and by time. A similar model quadratic in opiate duration was more powerfully predictive, suggesting the salience of the duration of opiate treatment (AIC 191·6898 and 191·5966, P=0·0116). Data suggest that increased length of opiate dependence is associated with advanced vascular stiffness and ageing and are therefore consistent with accelerated ageing organismally. The superiority of power functions of the opiate duration of exposure underscores the significance of the duration of treatment and of putative senescence induction.

Regaining control: The patient experience of supervised compared with unsupervised consumption in opiate substitution treatment

Supervised consumption of opiate substitution treatment is standard practice in the UK yet little is known about the patient experience of this treatment modality. This study aimed to assess the patient experience of receiving supervised compared with unsupervised consumption of methadone or buprenorphine. A qualitative study utilising a grounded theory approach to analysis. Participants (29) were theoretically sampled from 293 opioid-dependent patients entering a randomised controlled trial of opiate substitution treatment across four urban and community drug treatment services in England. Multidisciplinary staff were recruited for interviews and focus groups (55). Supervised consumption was accepted by patients, despite causing practical limitations and raising issues of privacy and stigma. Patients recognised that establishing a daily routine away from illicit drugs was useful early in treatment. However, having flexibility to move away from supervision was important. Unsupervised patients reported that they ultimately preferred this treatment approach and appreciated the trust and sense of reward that unsupervised treatment bought. Clinicians expressed confidence in supervised prescribing and reduced risk for their patients, but also concern that a minority of individuals may remain inappropriately supervised for lengthy time periods. This study provides an important patient perspective and is the first in-depth qualitative investigation directly comparing supervision with unsupervised treatment to consider both patient and professional perspectives. Overall, our qualitative findings suggest that flexibly timed discontinuation of supervision may have positive benefits.

Ergebnisse wiederholter qualifizierter stationärer Opiatentzugsbehandlungen bei innerhalb eines Jahres mehrfach aufgenommenen Patienten

Do patients readmitted to inpatient detoxification within a short time show favourable treatment outcomes? Data were from a treatment facility providing for comprehensive opiate detoxification treatment. It was recorded whether consecutively admitted patients (n = 169) were re-admitted within 1 year after discharge. Outcome data were collected from patient files. There were 43 % readmissions within 1 year. Readmission was predicted by lack of transfer to drug-free follow-up treatment, longer duration of opiate dependence, and comorbid axis 1 disorders. Rates of regular completion were 42 % for the index treatment and 31 % for the first readmission treatment. Of those repeaters who had prematurely terminated their first treatment, 77 % also did not complete their second treatment. Treatment programs have to prepare for increased rates of comorbid psychiatric disorders in early treatment repeaters. Outcome quality of repeated treatments was not significantly worse compared to index treatment. However, for a subgroup of patients opiate detoxification may not serve as a gateway to abstinence oriented treatment, but as a means of harm reduction.

Public opinion of drug treatment policy: Exploring the public's attitudes, knowledge, experience and willingness to pay for drug treatment strategies

BackgroundResearch evidence is strong for opiate replacement treatment (ORT). However, public opinion (attitudes) can be at odds with evidence. This study explored the relationships between, attitudes, knowledge of drugs and a range of socio-demographic variables that potentially influence attitude. This is relevant in the current policy arena in which a major shift from harm reduction to, rehabilitation is underway. MethodsA cross sectional postal questionnaire survey in Scotland was conducted where the drug, treatment strategy has changed from harm-reduction to recovery-based. A random sample (N=3000), of the general public, >18 years, and on the electoral register was used. The questionnaire was largely structured with tick box format but included two open questions for qualitative responses. Valuation was measured using the economic willingness-to-pay (WTP) method. ResultsThe response rate was 38.1% (1067/2803). Less than 10% had personal experience of drug, misuse but 16.7% had experience of drug misuse via a friend/acquaintance. Regression modelling revealed more positive attitudes towards drug users in those with personal experience of drug misuse, (p<0.001), better knowledge of drugs (p=0.001) and higher income (those earning >£50,000 per, annum compared to <£15K; p=0.01). Over half of respondents were not willing to pay anything for drug treatment indicating they did not value these treatments at all. Respondents were willing-to-pay most for community rehabilitation and least for methadone maintenance treatment. Qualitative analysis of open responses indicated many strong negative attitudes, doubts over the efficacy of methadone and consideration of addiction as self-inflicted. There was ambivalence with respondents weighing up negative feelings towards treatment against societal benefit. ConclusionsThere is a gap between public attitudes and evidence regarding drug treatment. Findings suggest a way forward might be to develop and evaluate treatment that integrates ORT with a community rehabilitative approach. Evaluation of public engagement/education to improve knowledge of drug treatment effectiveness is recommended.

HIV/AIDS trends in China

HIV/AIDS trends in China

Disaccharides in Urine Samples as Markers of Intravenous Abuse of Methadone and Buprenorphine

Methadone and buprenorphine are commonly used as oral substitutes in opiate maintenance programs to treat persons who are dependent on heroin. During these programs, patients are not allowed to continue using illicit drugs. Abstinence can easily be monitored by urine tests with immunochemical methods. It is well known that the intravenous abuse of heroin substitutes like methadone or buprenorphine has become common as well. The methadone-prescribing physician has no opportunity to check whether the opiate maintenance treatment patient takes his substitution medicines orally as intended or continues with his intravenous misuse now substituting the methadone instead of injecting heroin. In Germany, substitutes are available as liquids and tablets that contain carbohydrates as adjuvants. Sucrose is used to increase viscosity in liquids, while lactose is needed for pressing tablets (e.g., Methaddict® and Subutex®). In case of oral ingestion, disaccharides are broken down into monosaccharides by disaccharidases in the small intestine. These monosaccharides are absorbed into the blood stream by special monosaccharide transporters. Disaccharidases do not exist in blood, thus sucrose and lactose are not split if substitute medicines are injected intravenously. Our assumption, therefore, was that they are excreted unchanged in urine. We investigated a method for the detection of disaccharides in urine as markers of intravenous abuse of substitutes. Urine samples of 26 intravenous substitute abusers showed all positive results for lactose (76.9%) and/or sucrose (73.1%). The method is assumed to be useful to detect intravenous abuse of substitutes.

Treatment expectations and satisfaction of treatment‐refractory opioid‐dependent patients in RIOTT, the Randomised Injectable Opiate Treatment Trial, the UK's first supervised injectable maintenance clinics

The study investigates patients' pre-treatment expectations of, and post-treatment satisfaction with, supervised injectable opiate treatment delivered within UK's first such clinics within the Randomised Injectable Opiate Treatment Trial (RIOTT) (ISRCTN0133807). Data were collected from 127 chronic heroin addicts recruited to RIOTT and randomised to receive supervised injectable (heroin or methadone) treatment or optimised oral maintenance treatment at supervised injectable maintenance clinics in London, Darlington and Brighton. Of 127 RIOTT patients, 113 (89%) provided responses to structured enquiry about treatment expectations, and 94 (74%) subsequent responses about treatment satisfaction (at six months). Patients were hoping that injectable heroin treatment would: reduce substance misuse (81%); help achieve normality, routine and structure (16%); and increase education and work prospects (15%). At six months, an area of treatment satisfaction most commonly reported by all three trial groups was reduced substance misuse (supervised injectable heroin 59%, supervised injectable methadone 56%, optimised oral methadone 54%). Most found supervision acceptable, but some desired modifications were also identified. Patients previously considered non-responsive to treatment appear to have similar treatment expectations and aspirations as other drug users in treatment. Supervised injectable opioid treatment patients consistently reported treatment satisfaction but also that more could be done to optimise aspects of current arrangement. This raised the challenging issue of the extent to which opinions of patients need to be taken into consideration in shaping future treatment provision. Future research may need to examine the extent of expectations 'fit' and the relationship between treatment sought and received.

Medical drug abuse and aging

Drug addiction is often underestimated among the aged. Opiate drugs (mostly pain killers) are the most frequently implicated in drug addiction after benzodiazepines (BZD) in the aged. The subjects aged of 65 years or more are the most represented among the BZD users in France. Frequency of BZD use varies according to various studies from 39 to 55% in this age group. Leading a lonely life is associated with the use of psychotropic drugs among retired people (OR=1.7). Vulnerability at this age must take into account not only polypathology, but also the faster aging of a minority of the population under opiate drugs substitution treatment (OST), more subjects to drugs interaction. Drug addiction among elderly often reflects the drift of "lawful" doctor's instructions that leads to an increase in drugs use. The difficulty has to do with a lack of specificity of diagnosis of addiction at this age, but perhaps also with physicans'instructions in the aged. Some authors suggest that continued and prolonged use should be considered the main criterion for BZD addiction at this age, with or without increase in doses and failed attempt at cessation. Besides, the prescription of BZD increases after retirement and loneliness.

Economic evaluation: A comparison of methadone versus buprenorphine for opiate substitution treatment

BackgroundThe cost of opiate substitution is usually considered lower in cost when methadone is used, as compared to that of buprenorphine, however the overall cost effectiveness of substitution programmes comparing the two drugs remains largely unknown. MethodsWe evaluated the treatment cost and effectiveness of methadone and buprenorphine when used in an opiate substitution programme in Norfolk, UK. All programme costs, estimated from the perspective of the drug treatment clinic, were collected on 361 opiate-dependent participants over a six-month period. Total costs comprised medication (methadone or buprenorphine) costs, pharmacy supervision and dispensing costs, and drug service clinic costs. Effectiveness was measured in terms of (1) each programmes ability to retain participants in the programme for six months, and (2) the ability of the programme to accomplish complete abstinence from illicit opiate consumption. ResultsOverall, mean medication-only costs of methadone were lower than that of buprenorphine, however, pharmacy and clinic costs were lower for the buprenorphine programme. The covariate-adjusted mean total cost of the two programmes was not significantly different. Mean six-month retention rates were higher on the methadone programme, therefore, the methadone programme “dominates” the buprenorphine programme as it was slightly more effective for the same cost. Conversely, when ability to stop taking illicit opiates concomitant with opiate substitution medication was considered, the buprenorphine programme was more effective with an additional cost of £903 per individual who stopped illicit opiate use. ConclusionsThe provision of buprenorphine should be considered an appropriate treatment if cessation of illicit opiate use, concomitant with programme retention is considered an important outcome.

Structural barriers in the context of opiate substitution treatment in Germany - a survey among physicians in primary care

BackgroundOpiate substitution treatment (OST) is the most widely used treatment for opioid dependence in Germany with substantial long-term benefits for the patient and for society. Due to lessened restrictive admission criteria, the number of registered OST patients in Germany has increased continuously in the recent years, whereas the number of physicians providing OST has remained constant. Previous data already indicated a deteriorating situation in the availability or quality of OST delivered and that structural barriers impede physicians in actively providing OST. The present survey among a sample of primary care physicians in Germany aimed to identify and assess potential structural barriers for the provision of health care in the context of OST.MethodsAn anonymous written questionnaire was sent out to a sample of 2,332 physicians across Germany providing OST. Physicians contacted were identified through databases of the Federal State Chambers of Physicians and/or of the Federal Associations of Statutory Health Insurance Physicians. Data obtained were analysed descriptively.ResultsThe response rate was 25,5% and the majority of 596 physicians sampled viewed substantial problems in terms of the regulatory framework of OST care in the German context. Furthermore, financial remuneration, insufficient qualification, as well as inadequate interdisciplinary cooperation in the treatment of comorbidities of opiate substituted patients were regarded as problematic. The number of physicians providing OST in Germany is expected to substantially decrease in the near future.ConclusionDespite less restrictive admission criteria for OST in Germany, the legal regulation framework for OST is still a limiting factor through raising concerns on the provider and consumer side to be unable to adhere to the strict rules. To avoid future shortages in the provision of OST care on the system level in Germany, revisions to the legal framework seem to be necessary. In regards to adequate care for drug use-related infectious diseases and psychiatric comorbidities commonly found in opiate substituted patients, efforts are required to improve professional qualifications of physicians providing OST as well as respective interdisciplinary collaboration.

Problem alcohol use among problem drug users in primary care: a qualitative study of what patients think about screening and treatment

BackgroundProblem alcohol use is common and associated with considerable adverse outcomes among patients who attend primary care in Ireland and other European countries for opiate substitution treatment. This paper aims to describe patients’ experience of, and attitude towards, screening and therapeutic interventions for problem alcohol use in primary care.MethodsThis qualitative study recruited problem drug users (N = 28) from primary care based methadone programmes in the Ireland’s Eastern region, using a stratified sampling matrix to include size of general practice and geographical area. Semi-structured interviews were conducted and analysed using thematic analysis, and audited by a third reviewer.ResultsWe identified three overarching themes relevant to the purpose of this paper: (1) patients’ experience of, and (2) attitude towards, screening and treatment for problem alcohol use in primary care, as well as their (3) views on service improvement. While most patients reported being screened for problem alcohol use at initial assessment, few recalled routine screening or treatment. Among the barriers and enablers to screening and treatment, patients highlighted the importance of the practitioner-patient relationship in helping them address the issue. Nevertheless, patients felt that healthcare professionals should be more proactive in the management of problem alcohol use at a primary care level and that primary care can play an important role in their treatment.ConclusionsProblem alcohol use is an important challenge in the care of problem drug users. While primary care is well placed to address this issue, little data has reported on this topic. The development of interventions which promote screening and brief interventions in practice are likely to benefit this at-risk group and further research and education, that help achieve this goal, are a priority. Strategies such as dissemination of clinical guidelines, educational videos, academic detailing and practice visits, should be explored.

Problem alcohol use among problem drug users: development and content of clinical guidelines for general practice

Problem alcohol use is common and associated with considerable adverse outcomes among patients who attend primary care in Ireland and other European countries for opiate substitution treatment. This paper aims to describe the development and content of clinical guidelines for the management of problem alcohol use among this population. The guidelines were developed in three stages: (1) identification of key stakeholders, (2) development of evidence-based draft guidelines, and (3) determination of a modified 'Delphi-facilitated' consensus among the group members. The guidelines incorporate advice for physicians on all aspects of care, including (1) definition of problem alcohol use among problem drug users, (2) alcohol screening, (3) brief intervention, and (4) subsequent management of patients with alcohol dependence. Primary care has an important role to play in the care of problem alcohol use among problem drug users, especially opiate substitution patients. Further research on strategies to inform the implementation of these guidelines is a priority.

Predicting biopsychosocial outcomes for heroin users in primary care treatment: a prospective longitudinal cohort study

Opiate substitution treatment for heroin users reduces mortality, illicit drug use, crime, and risk-taking behaviour, and improves physical, mental and social functioning. Few extended studies have been carried out in UK primary care to study factors predicting recovery. To establish whether primary care opiate substitution treatment is associated with improvements in outcomes over 11 years, in delivering recovery, and to identify predictive factors. A prospective longitudinal cohort study, with repeated measures in the Primary Care Addiction Service, Sheffield, 1999-2011. A total of 123 eligible patients were assessed using the Opiate Treatment Index at entry to treatment and at 1, 5, and 11 years. Clinical records were used to assess factors including employment and discharge status. At 11 years, there was a high rate of drug-free discharge (22.0%) and medically-assisted recovery (30.9%), and low mortality (6.5%). Continuous treatment was associated with being discharged drug free (P = 0.005). For those still in treatment, there were highly significant reductions in heroin use and injecting, and significantly improved psychosocial functioning. There were strong positive correlations between mental health, physical health, and social functioning. Patients in employment had significantly better psychological and social functioning (P = 0.017, P = 0.007, respectively). Opiate substitution treatment is associated over 11 years with full recovery, drug-free discharge and medically-assisted recovery. There is a strong association between the psychosocial variables, suggesting that intervention in any one of these areas may have extended benefits, by impacting on related variables and employment. The best predictor of a drug-free discharge was continuous uninterrupted treatment.

Efforts to Reduce Overdose Deaths

The recent article by Schwartz et al. addresses the intersection of two important public health issues: opiate substitution therapy and fatal heroin overdose.1 In the United States, drug overdose is responsible for more than 36 000 deaths annually2 and is the leading cause of death among illicit drug users. Baltimore, Maryland, has one of the highest per capita heroin addiction rates in the nation, with an estimated prevalence of heroin use in 10% of the population.3 Schwartz et al. conducted a 15-year ecological analysis in Baltimore and found that increases in buprenorphine and methadone treatment with concurrent decreases in overdose deaths, controlling for heroin purity. Along with previous research,4 this study demonstrates the far-reaching benefits of opiate agonist treatment. In Baltimore, an estimated 34% of 68 000 drug users were in drug treatment in 2011, with heroin being the primary drug of abuse.5 The magnitude of out-of-treatment drug users in Baltimore and in the United States underscores the need for overdose prevention efforts targeting this population. Furthermore, out-of-treatment, long-term injection drug users (IDUs) are at greatest risk for overdose.6,7 As Schwartz et al. noted, periods of abstinence resulting from recent incarceration or drug treatment are chief overdose risk factors, given associated decreases in tolerance.8,9 These facts speak to the importance of overdose prevention among active IDUs. Capital City Care, a medical marijuana dispensary, is shown in Washington, DC, on April 15, 2013, prior to the store's opening. Three years after Washington, DC, legalized medical marijuana, three stores are set to open, allowing patients with HIV/AIDS, ... As of 2012, there were an estimated 188 overdose prevention education and naloxone distribution programs (OPEND) in the United States.2 OPEND programs train peer drug users how to prevent overdoses and administer naloxone in the event of an overdose. Naloxone is a short-acting opiate antagonist that reverses the effects of respiratory depression commonly caused by opiate overdose.7 Since 2004, Baltimore’s OPEND program, Staying Alive, has reached 35 000 individuals including an estimated 10 000 IDUs, 1200 medical and drug treatment providers, and 8500 jail inmates. Staying Alive has distributed 4000 vials of naloxone, and 250 reversals have been reported. Between 2003 and 2009 (half of the study period examined in Schwartz et al.), Staying Alive distributed 1263 naloxone vials and 196 reversals were reported. We commend Schwartz et al. for their study, which highlighted important public health programs that appear to reduce overdose mortality. We believe that both OPEND and increased availability of opiate substitution therapy have contributed to decreases in overdose mortality in Baltimore. We think that both are necessary for a holistic approach to the issue of overdose.

Cycles de traitement par médicament de substitution aux opiacés dans une cohorte de patients suivis 5 ans en médecine ambulatoire

To describe opiate substitution treatment (OST) cycles in a five year followed-up cohort of patients initiating OST during 5 years in ambulatory practice.Data were extracted from Health Insurance System Database from January 1(st) 2005 to December 31(st) 2010 for "Haute Garonne" (South Western France area, 1 million inhabitants). Patients starting OST were included. Drop-outs were identified throughout the follow-up.Five hundred patients were included, 72% of men, median age of 33 years. Median number of OST cycles was 2 [1; 3] on 5 years. Median duration of first OST cycle was 214 [77; 689] days. Median delay between first and second OST cycle was 80 [23; 241] days. Retention rate at one year was 38.2%.More than 50% of patients had at least 2 cycles of OST.

Use of Narcotics Contracts

Narcotics contracts, which stipulate patient responsibilities in exchange for opiate treatment of pain, may strike some patients as onerous, but they are a good way of reducing the risk of abuse or diversion of prescription drugs while still ensuring patients get pain relief.

Chronic non-cancer pain and six-month follow-up outcomes among community-based opiate addiction treatment clients on methadone

Individuals who seek medication-assisted treatment for opiate addiction are generally prescribed methadone along with behavioral counseling at a licensed opiate treatment program (OTP). For OTP clients who also have chronic non-cancer pain (CNCP), the disease of addiction is treated, but the disease of CNCP may not be addressed. Though connecting opioid dependence and CNCP may seem obvious since opioids produce both analgesia and euphoria, limited data is available on their co-occurrence and the impact on treatment outcomes.

Ligand‐induced μ opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl

Morphine differs from most opiates its poor ability to internalize μ opioid receptors (μORs). However, chronic treatment with morphine produces adaptational changes at the dynamin level, which enhance the efficiency of acute morphine stimulation to promote μOR internalization in enteric neurons. This study tested the effect of chronic treatment with fentanyl, a μOR-internalizing agonist, on ligand-induced endocytosis and the expression of the intracellular trafficking proteins, dynamin and β-arrestin, in enteric neurons using organotypic cultures of the guinea pig ileum. In enteric neurons from guinea pigs chronically treated with fentanyl, μOR immunoreactivity was predominantly at the cell surface after acute exposure to morphine with a low level of μOR translocation, slightly higher than in neurons from naïve animals. This internalization was not due to morphine's direct effect, because it was also observed in neurons exposed to medium alone. By contrast, D-Ala2-N-Me-Phe4-Gly-ol5-enkephalin (DAMGO), a potent μOR-internalizing agonist, induced pronounced and rapid μOR endocytosis in enteric neurons from animals chronically treated with fentanyl or from naïve animals. Chronic fentanyl treatment did not alter dynamin or β-arrestin expression. These findings indicate that prolonged activation of μORs with an internalizing agonist such as fentanyl does not enhance the ability of acute morphine to trigger μOR endocytosis or induce changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by chronic opiate treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization.

Neurobehavioural development of preschool‐age children born to addicted mothers given opiate maintenance treatment with buprenorphine during pregnancy

To study the neurobehavioural development and somatic growth of children at preschool-age born to opioid-addicted mothers given opiate maintenance treatment (OMT) with buprenorphine during pregnancy. Twenty-eight children, whose 21 opiate-addicted mothers were treated with OMT during pregnancy and accepted participation to the study, went through a battery of neurobehavioural tests (WPPSI-R, McCarthy, BROWN and SDQ). Twenty-five children fulfilled the tests at an age of 5-6 years. The children showed evidence of serious visual motor and attention problems in the field of performance (WPPSI-R scales) and major problems in the field of motor skills and memory abilities (McCarthy Scales). The results of behavioural tests also showed significantly elevated levels of hyperactivity, impulsivity and attention problems on the attention deficit hyperactivity disorder (ADHD) scale in BROWN and in SDQ tests estimated by the teachers, while the parents estimated no problems for their children. Regarding the outcomes, there were no significant differences in terms of neonatal abstinence syndrome, gender or socio-economic factors. The somatic growth of the children corresponded to the mean values of the normal population in weight, length and head circumference at birth and at preschool-age, respectively. Children to opiate-addicted mothers with buprenorphine maintenance treatment during pregnancy constitute a risk population, which should be recognized before start of the school. Whether the effects are associated with buprenorphine exposition during foetal life or not are discussed and need further investigation.