Management of Erectile Dysfunction (Review date December 2013)
ERECTILE DYSFUNCTION POLICY.
OUTLINE OF THIS POLICY
The attached policy outlines guidance on Erectile Dysfunction management in Walsall.
RECOMMENDATIONS
JMMC to agree on the policy for Erectile Dysfunction, for diagnosis and management Clinicians to use the International Index for Erectile Function 5 (IIEF5) and depression
tools, i.e. PHQ9, for assessing patients with psychological distress related to erectile
STAKEHOLDER CONSULTATION
The following people have been consulted for this revision:
Bharat Patel: Head of Medicines Management Dr Narinder Sahota: Medical Director Mr Suresh Ganta: Consultant Urologist Dr Joseph Arumainayagam: Consultant Genito-Urinary Medicine Medicines Management Quality Board: Will Willson, Dr Paul Giles Dr Jayant Gupta: Consultant Cardiologist
Management of Erectile Dysfunction (Review date December 2013)
1. ERECTILE DYSFUNCTION POLICY.
1.1 BASIS OF THIS POLICY The total male population of Walsall was 125,100 in 20101. It was stipulated by the
Massachusetts Male Aging Study2 that 17% of males aged 40-70 will have mild erectile
dysfunction, 25% will have moderate erectile dysfunction and 10% will have severe erectile
dysfunction. Furthermore it was also observed that the incidence of complete erectile
dysfunction at age 40 was 5% which increased to 15% at age 702. This study equates to
about 26 new cases annually per 1,000 men. Whichever study, country or methodology is
used, this is clearly a significant condition likely to present regularly to a GP on average
between 1 and 4 times per month. The total spend on erectile dysfunction drugs in Walsall
PCT was £381,752.99 in 2010-20113, which is equivalent to 0.9% of the total spend in
The Department of Health guidance issued in 1999 needs revision but until this is done, this
document has been produced to aid in the diagnosis, management and aftercare of patients
with erectile dysfunction in the Walsall tPCT 4(a)
1.1.1.
According to HSC1999/148, general practitioners are limited in their use of NHS prescriptions
for the treatment of erectile dysfunction. They may issue NHS prescriptions (endorsed “SLS”)
to those men who in their clinical judgement are suffering from erectile dysfunction and have
any of the fol owing medical conditions: diabetes, multiple sclerosis, Parkinson’s disease,
poliomyelitis, prostate cancer, prostatectomy, radical pelvic surgery, renal failure treated by
dialysis or transplant, severe pelvic injury, single gene neurological disease (e.g. Huntington’s
disease), spinal cord injury and spina bifida4(a).
1.1.2
Those men receiving a course of NHS drug treatment for erectile dysfunction (e.g. Caverject,
Erecnos, MUSE, Viagra or Viridal) on 14 September 1998 will continue to be eligible to
receive drug treatment, including Sildenafil from their GP. One NHS treatment per week
should normally be considered adequate 4(a), if more is required the GP should prescribe that
1.1.3
General Practitioners and Hospital Clinicians are free to issue private prescriptions to NHS
patients for other medical conditions resulting in erectile dysfunction. Again, one NHS
treatment per week should normally be considered adequate. They must not charge for this
Management of Erectile Dysfunction (Review date December 2013)
1.2 COMMISSIONING OF SERVICES
The tPCT may also commission the prescribing of medications initiated by specialist services.
This may include the commissioning of services such as psychosexual counselling. Services
aimed at the cessation of smoking and alcohol may be utilised when tackling lifestyle issues
1.3 TREATMENT ALTERNATIVES The tPCT may also commission implants or surgical interventions for patients who would be
eligible for medical treatments, if those treatments would be considered clinically preferable
on an individual patient basis. Such treatments may be commissioned only on the prior
authorisation of the PCT; which will consider issues of appropriateness, effectiveness and
priority, and may consider clinical advice about the patient, in reaching their judgement.
1.4 SPECIALIST REFERRAL Most men suffering from erectile dysfunction suffer distress. This is not necessarily a direct
indication for referral to secondary care although this was outlined in the Health Service
Circular in 19994(c). It has been recommended by the tPCT that the GP can make an
assessment of psychological distress, using validated tools (i.e. IIEF5 and PHQ9 see
addendum 4 ), and prescribe treatment on the NHS if there is severe psychological distress
as a result of erectile dysfunction. They must however follow up the patient to monitor
treatment and if there is treatment failure, may wish to refer to secondary care (as outlined in
the treatment pathway in this document).
Specific other indications for specialist referral include the following6:
1. In situations where laboratory findings are ambiguous or to identify the need for
more comprehensive management, e.g. suspected hypogonadism or complex
2. Where there is primary ED, e.g. in a young patient with pelvic / perineal trauma
3. In patients with significant penile curvature (e.g. Peyronie’s disease and
Any patient with erectile dysfunction may make use of whatever NHS psychological and
psychosexual counselling services are available at that time within the tPCT4(b).
Management of Erectile Dysfunction (Review date December 2013)
1.5 IATROGENIC CAUSES There are a number of drugs commonly associated with sexual dysfunction and the likelihood
that this may be a contributory factor should first be sought out by the GP. The following table
describes the effects of certain medication of sexual function but it by no means replaces
clinical judgement. Most medications will need continuation due to other underlying medical
conditions particularly coexisting IHD 7,8.
KEY: + Possible link with ED but not proven, + Weak association with very few cases reported, ++ Erectile
dysfunction well recognised, but not frequent, +++ Erectile dysfunction frequent and well recognised. 7,8
Strength of Medication Type of sexual dysfunction Association Diuretics Sympatholytics
Erectile dysfunction, ejaculatory dysfunction
B-Blockers (particularly non-selective agents)
Lithium Carbonate Antipsychotic agents Antidepressants
Erectile dysfunction, ejaculatory dysfunction
Anxiolytic agents
Management of Erectile Dysfunction (Review date December 2013)
2. EVALUATION OF PATIENTS WITH ERECTILE DYSFUNCTION9,10 ↔↔↕ Patient presents with possible erectile dysfunction. Erectile dysfu nction is the inability to develop and maintain an erection for satisfactory sexual intercourse or activity. Take a detailed history to rule out other sexual problems such as premature ejaculation, loss of libido etc, relationship problems. Are there any clues to a psychogenic or organic cause? SUGGESTS PSYCHOGENIC SUGGESTS ORGANIC
Lack of tumescence but normal Ejaculation and Libido
pontaneous/self stimulated/waking erections.
Risk factor in current or past history (with reference to
Premature ejaculation or inability to ejaculate.
cardiovascular, endocrine and neurological systems.
Operations, radiotherapy or trauma to pelvis/scrotum.
Current medication associated with erectile dysfunction.
Smoking, alcohol, recreational or body building drug use.
See addendum 1 EXAMINATION
Examin ation of genitalia looking for abnormalities on testicular size, fibrosis of penile shaft and foreskin retractibility.
Focus on other systems depending upon the history e.g. neurological, peripheral vascular, cardiovascular.
See addendum 2 INVESTIGATIONS
Urine dipstick for glucose and/or protein.
Treat any medical condition discovered by routine blood testing accordingly Measure morning serum testosterone (see addendum 3) Meas ure prolactin if patient taking antipsychotics MANAGEMENT
Does the patient have any of the following?
Diabetes, Multiple sclerosis, poliomyelitis, Parkinson’s disease, prostate cancer, severe pelvic
injury, spina bifida, spinal cord injury or a single gene neurological disease
Have had radial pelvic surgery, prostatectomy (including TURP) or kidney transplant
Were receiving Caverject, Erecnos. MUSE, Viagra, Viridal for ED on the NHS on 14th Sept 1998
Are suffering severe distress as a result of ED: May be treated in primary care and do not necessarily need referral to secondary care as outlined in government guidelines (see Addendum 4) IS THE PATIENT PRESENTING WITH ERECTILE DYSFUNCTION WITH NO CLEAR CONTRIBU CULAR RISK. (See Addendum dix 2). IF I NTERME DIATE O R HIGH RISK, REFER FOR FURTHER INVESTIGATION. See addendum Is the patient taking Sildenafil 50mg Nitrates? See Addendum 10 Treatment Failure improvement Sildenafil 100mg Treatment Failure See Addendum See addendum Vardenafil Tadalafil
Ambiguous lab f A SECONDARY CARE
Primary ED, e.g. in a young patients with pelvic /
Treatment Failure Treatment Failure See Addendum 12
Penile curvature (e.g. Peyronie’s disease).
Management of Erectile Dysfunction (Review date December 2013)
3. ADDENDUM
Primary hypogonadism is suggested by a history of testicular trauma, orchitis,
testicular surgery or torsion, chemotherapy or irradiation.
Hypothalamic-pituitary tumours are suggested by symptoms such as headaches,
impaired visual fields, polydipsia and polyuria, or evidence of pituitary hormone
excess such as acromegaly, Cushing's disease or hyperprolactinaemia.
2. Consider using validated questionnaires, such as the International Index for Erectile
Function 5 (IIEF5), to assess: erectile function, orgasmic function, sexual desire,
ejaculation problems, intercourse problems, overall satisfaction (appendix 1). The
IIEF 5 questionnaire is a valid tool for diagnosing the presence and severity of erectile
dysfunction11. It is intended to complement the patient history and physical
examination. A score of 21 or less reveals some degree of erectile dysfunction. It is a
useful instrument to monitor the effect of treatment on erectile dysfunction12.
3. Universal measurement of testosterone levels is recommended by European
guidelines13, but is at odds with North American guidelines which recommend
selective screening14. However, the consensus opinion of British Society for Sexual
Medicine (BSSM) was that testosterone screening was pragmatic in light of the fact
that testosterone deficiency is reversible, and can have a negative impact on
phosphodiesterase-5 inhibitor efficacy15.
4. Guidelines suggest the GP is recommended to refer if severe distress is suspected5.
It has been agreed by the tPCT that the GP can make an assessment of
psychological distress and prescribe treatment on the NHS if it is sufficient to warrant
it. The Department of Health recommends that when determining whether a patient is
suffering from severe distress the following criteria should be considered: significant
disruption to normal social and occupational activity; marked effect on mood,
Management of Erectile Dysfunction (Review date December 2013)
behaviour, social and environmental awareness; and marked effect on interpersonal
Practitioners can use tools, such as PHQ9 questionnaire to identify psychological
distress in the community, which takes into consideration the above criteria. This
should be used in conjunction with the IIEF-5 tool.
5. ED is a surrogate marker for cardiovascular disease and also there is a group of
patients who are at significant risk of MI after exertion of sexual activity and may need
to be assessed prior to recommending treatment for ED. Low risk patients may be
treated in primary care. i.e. post revascularization after CABG and low risk of
6. Sildenafil, tadalafil, and vardenafil are potent, reversible, competitive inhibitors of
phosphodiesterase 5 (PDE5). A systematic review has found all PDE-5 inhibitors
consistently improved erectile functioning compared to placebo: 73-88% who
received PDE-5 inhibitors compared to 26-32% who received placebo17. At this time,
there is insufficient evidence to support the superiority of one agent over the others17.
Sildenafil is recommended first-line as it has been in use longer and is well
established; additionally it will be of benefit from an economic perspective.
7. Sildenafil is to be taken 1 hour before sexual activity and onset may be delayed when
taken with food. Tadalafil has little interaction with food and effect may persist for
longer than 24 hours. Vardenafil may have a delayed onset of action if taken with
food with a high fat contact. These interactions must be considered as a potential
8. All PDE5 inhibitors appear to have some interaction with alpha blockers, which under
some conditions may result in orthostatic hypotension. Sildenafil labelling currently
describes a precaution advising that 50 or 100 mg (not 25 mg) of sildenafil should not
be taken within a 4-hour window of an alpha blocker. Vardenafil is absolutely
contraindicated with alpha blockers in the USA. However, the co-administration of
Vardenafil with Tamsulosin is not associated with clinical significant hypotension18.
Tadalafil is contraindicated in patients taking alpha blockers, except for Tamsulosin
9. There is some evidence to suggest that vardenafil has a role in patients who are non-
responders and diabetics. In light of this, one has the option of considering this as the
first line drug in Diabetics in place of sildenafil19.
10. Follow-up should ideally take place within 6 weeks of starting treatment, although
expert opinion recommends that at least 8 tablets should be taken before follow-up11.
Management of Erectile Dysfunction (Review date December 2013)
If treatment has been ineffective, there is a need to check that the medication has
been properly prescribed and correctly used (i.e. that there is adequate sexual
stimulaton and dosage and enough time between taking the medication and an
11. Second-line tadalafil or vardenafil should be considered. As a systematic review has
shown similar efficacy and safety profile between the oral PDE 5 inhibitors17; it is
recommended to inform the patients about the effects (short- or long-acting) and
possible disadvantages of each drug. The frequency of intercourse (occasional use or
regular therapy, 3-4 times weekly) and personal experience will determine the drug of
12. Since tadalafil has a longer duration of action, if it is taken once every 24 hours (but
not every day), the effect of intermittent dosing may persist for longer than 24 hours20.
Daily dosing with tadalafil may salvage some non-responders to intermittent dosing21.
For patients who anticipate sexual activity at least twice weekly, 5 mg once daily can
be taken, reduced to 2.5 mg once daily according to response.
Management of Erectile Dysfunction (Review date December 2013)
APPENDIX 1 International Index of Erectile Function (IIEF) 5 22 Over the past six
The IIEF-5 score is the sum of questions 1 to 5. The lowest score is 5 and the
Score 22-25 No ED 17-21 Mild ED 12-16 Mild to moderate ED 8-11 Moderate ED 5-7
Management of Erectile Dysfunction (Review date December 2013)
APPENDIX 2: CARDIAC RISK STRATIFICATION16 Low-risk category Intermediate-risk category High-risk category
Moderate, stable angina*
being treated)* CAD, coronary artery disease; CHF, congestive heart failure; LVD, left ventricular dysfunction; MI, myocardial infarction; NYHA, New York Heart Association. *Refer to Canadian Cardiovascular Society Angina Grading Scale: mild stable angina = class I and II, moderate = class III Low-risk category
The low-risk category includes patients who do not have any significant cardiac risk
associated with sexual activity. The ability to perform exercise of modest intensity without
symptoms typically implies low risk. Based upon current knowledge of the exercise demands
or emotional stress associated with sexual activity, no special cardiac testing or evaluation is
indicated for these patients before the initiation or resumption of sexual activity or therapy for
Intermediate-risk, or high-risk, category
The intermediate- or high-risk category consists of those patients whose cardiac condition is
uncertain, or whose risk profile is such that further testing or evaluation is indicated before
the resumption of sexual activity. Based upon the results of testing, these patients may be
subsequently assigned to either the high- or low-risk group. Cardiology consultation in some
cases may help the GP in determining the relative safety of sexual activity for the individual
Management of Erectile Dysfunction (Review date December 2013)
REFERENCES
1. Office for National Statistics. Mid-2010 Population Estimates: Quinary age groups for local
authorities in the United Kingdom; estimated resident population. Office for National
2. Feldman HA et al. Impotence and its medical and psychosocial correlates: Results of the
Massachusetts Male Aging Study. J Urol 1994;151:54-61.
4. Department of health guidance, Health Service Circular:
(a) HSC 1999/115, 7th May 1999, (Information, General Health Services)
(b) HSC 1999/148, 30th June 1999 (Good practice and General Health Services)
(c) HSC 1999/177, 6th August 1999, (Guidance on patients with Severe Distress)
(Please note that these Circulars were due to be updated the following year but this was not done. As such the guidance from the Government is rather out of date).
5. Hackett G, Kell P, Ralph D, Dean J, Price D, Speakman M, et al. British society for sexual
medicine guidelines on the management of erectile dysfunction. J Sex Med 2008;5(8):1841-
6. Von Keitz A, The Management of Erectile Dysfunction in The Community. Int J Impotence Research, S45-S51;13 Suppl 3:2001.
7. Thomas J, Pharmacological Aspects of Erectile Dysfunction, Jpn.J.Pharmacol 2002;
8. British National Formulary (BNF). London: BMJ Group and RPS Publishing; September
9. UK Management guidelines for Erectile Dysfunction, Erectile Dysfunction Alliance 1998.
10. Muezzinoglu T et al, A relationship of Sex Hormone Levels and Erectile Dysfunction:
Which Tests Should Be Done Routinely? Yonsei Med J, 2007; 48(6):1015-1019.
11. Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2011.
12. Rosen RC, Riley A, Wagner G, Osterloh IH, et al. The international index of erectile
function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology
13. Wespes E, Amar E, Eardley I, Guiliano F, Hatzichristou D, Hatzimouratidis K, et al.
Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation.
European Association of Urology (EAU) 2009.
14. American Urological Association. Management of erectile dysfunction: an update.
15. Clinical Knowledge Summaries (CKS). Erectile dysfunction. Version 1.3. Newcastle upon
16. Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, et al.
Guidelines on erectile dysfunction, European Association of Urology (EAU) 2006.
Management of Erectile Dysfunction (Review date December 2013)
17. Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, Garritty C, Soares-
Weiser K, Daniel R, Sampson M, Fox S, Moher D, Wilt T. Oral phosphodiesterase-5 inhibitors
and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann
18. Auerbach SM, Gittelman M, Mazzu A, Cihon F, Sundaresan P, White WB. Simultaneous
administration of Vardenafil and tamsulosin does not induce clinically significant hypotension
in patients with benign prostatic hyperplasia. Urology, 2004;64:998-1003.
Comparing vardenafil and sildenafil in the treatment of men with erectile dysfunction
and risk factors for cardiovascular disease: a randomized, double-blind, pooled crossover
20. British National Formulary (BNF). BNF 62. London:BMJ Group and RPS Publishing; 2011.
21. McMahon C. Comparison of efficacy, safety, and tolerability of on-demand tadalafil and
daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2005;2(3):415-25.
22. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of
an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a
diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11(6):319-26.
J Musculoskel Neuron Interact 2003; 3(1):71-76 Original Article Bone mineral density in hypoparathyroid women on LT4 suppressive therapy. Effect of calcium and 1,25(OH)2 vitamin D3 treatment F. Hawkins1, F. Escobar-Jiménez2, E. Jfidar1, M.M. Campos2, M.B. L fi pez Alvarez1, G. Mart›nez D›az-Guerra1 1Service of Endocrinology, University Hospital 12 de Octubre, Madrid2Servi
Product information QuALitAtive And QuAntitAtive Adverse reactions Withdrawal periods immediate packaging ComPosition Hypersensitivity reactions (cattle), hepatotoxicity Cattle: Meat and offal - 35 days; Milk - 8 days. Amber coloured, glass type II vials containing each millilitre contains: Active substance: and haematologic effects have been reported, Pigs: Meat an
Management of Erectile Dysfunction (Review date December 2013)
ERECTILE DYSFUNCTION POLICY. 
Management of Erectile Dysfunction (Review date December 2013)
1. ERECTILE DYSFUNCTION POLICY. 
Management of Erectile Dysfunction (Review date December 2013)
1.2 COMMISSIONING OF SERVICES 
Management of Erectile Dysfunction (Review date December 2013)
1.5 IATROGENIC CAUSES 
Management of Erectile Dysfunction (Review date December 2013)
2. EVALUATION OF PATIENTS WITH ERECTILE DYSFUNCTION9,10 
Management of Erectile Dysfunction (Review date December 2013)
3. ADDENDUM 
Management of Erectile Dysfunction (Review date December 2013)
behaviour, social and environmental awareness; and marked effect on interpersonal
Practitioners can use tools, such as PHQ9 questionnaire to identify psychological
distress in the community, which takes into consideration the above criteria. This
should be used in conjunction with the IIEF-5 tool.
5. ED is a surrogate marker for cardiovascular disease and also there is a group of
patients who are at significant risk of MI after exertion of sexual activity and may need
to be assessed prior to recommending treatment for ED. Low risk patients may be
treated in primary care. i.e. post revascularization after CABG and low risk of
6. Sildenafil, tadalafil, and vardenafil are potent, reversible, competitive inhibitors of
phosphodiesterase 5 (PDE5). A systematic review has found all PDE-5 inhibitors
consistently improved erectile functioning compared to placebo: 73-88% who
received PDE-5 inhibitors compared to 26-32% who received placebo17. At this time,
there is insufficient evidence to support the superiority of one agent over the others17.
Sildenafil is recommended first-line as it has been in use longer and is well
established; additionally it will be of benefit from an economic perspective.
7. Sildenafil is to be taken 1 hour before sexual activity and onset may be delayed when
taken with food. Tadalafil has little interaction with food and effect may persist for
longer than 24 hours. Vardenafil may have a delayed onset of action if taken with
food with a high fat contact. These interactions must be considered as a potential
8. All PDE5 inhibitors appear to have some interaction with alpha blockers, which under
some conditions may result in orthostatic hypotension. Sildenafil labelling currently
describes a precaution advising that 50 or 100 mg (not 25 mg) of sildenafil should not
be taken within a 4-hour window of an alpha blocker. Vardenafil is absolutely
contraindicated with alpha blockers in the USA. However, the co-administration of
Vardenafil with Tamsulosin is not associated with clinical significant hypotension18.
Tadalafil is contraindicated in patients taking alpha blockers, except for Tamsulosin
9. There is some evidence to suggest that vardenafil has a role in patients who are non-
responders and diabetics. In light of this, one has the option of considering this as the
first line drug in Diabetics in place of sildenafil19.
10. Follow-up should ideally take place within 6 weeks of starting treatment, although
expert opinion recommends that at least 8 tablets should be taken before follow-up11.
Management of Erectile Dysfunction (Review date December 2013)
If treatment has been ineffective, there is a need to check that the medication has
been properly prescribed and correctly used (i.e. that there is adequate sexual
stimulaton and dosage and enough time between taking the medication and an
11. Second-line tadalafil or vardenafil should be considered. As a systematic review has
shown similar efficacy and safety profile between the oral PDE 5 inhibitors17; it is
recommended to inform the patients about the effects (short- or long-acting) and
possible disadvantages of each drug. The frequency of intercourse (occasional use or
regular therapy, 3-4 times weekly) and personal experience will determine the drug of
12. Since tadalafil has a longer duration of action, if it is taken once every 24 hours (but
not every day), the effect of intermittent dosing may persist for longer than 24 hours20.
Daily dosing with tadalafil may salvage some non-responders to intermittent dosing21.
For patients who anticipate sexual activity at least twice weekly, 5 mg once daily can
be taken, reduced to 2.5 mg once daily according to response.
Management of Erectile Dysfunction (Review date December 2013)
APPENDIX 1 
Management of Erectile Dysfunction (Review date December 2013)
APPENDIX 2: CARDIAC RISK STRATIFICATION16 
Management of Erectile Dysfunction (Review date December 2013)
REFERENCES 
Management of Erectile Dysfunction (Review date December 2013)
17. Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, Garritty C, Soares-
Weiser K, Daniel R, Sampson M, Fox S, Moher D, Wilt T. Oral phosphodiesterase-5 inhibitors
and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann
18. Auerbach SM, Gittelman M, Mazzu A, Cihon F, Sundaresan P, White WB. Simultaneous
administration of Vardenafil and tamsulosin does not induce clinically significant hypotension
in patients with benign prostatic hyperplasia. Urology, 2004;64:998-1003.
Comparing vardenafil and sildenafil in the treatment of men with erectile dysfunction
and risk factors for cardiovascular disease: a randomized, double-blind, pooled crossover
20. British National Formulary (BNF). BNF 62. London:BMJ Group and RPS Publishing; 2011.
21. McMahon C. Comparison of efficacy, safety, and tolerability of on-demand tadalafil and
daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2005;2(3):415-25.
22. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of
an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a
diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11(6):319-26.